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Ovarian cancer
Article (Accepted Version)
http://sro.sussex.ac.uk
Matulonis, Ursula A, Sood, Anil K, Fallowfield, Lesley, Howitt, Brooke E, Sehouli, Jalid and Karlan, Beth Y (2016) Ovarian cancer. Nature Reviews Disease Primers, 2. p. 16061. ISSN 2056-676X
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This is the author’s version of a work that was accepted for publication in Nature Reviews Disease
Primers. Changes resulting from the publishing process, such as peer review, editing, corrections,
structural formatting and other quality control mechanisms may not be reflected in this document.
Changes may have been made to this work since it was submitted for publication. A definitive version
was subsequently published in Nature Reviews Disease Primers 2016 Aug 25;2:16061. Doi:
10.1038/nrdp.2016.61
Ovarian cancer
Ursula A. Matulonis1*, Anil K. Sood2, Lesley Fallowfield3, Brooke E. Howitt4, Jalid Sehouli5 and
Beth Y. Karlan6
1 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue,
Boston, Massachusetts 02215, USA
2 Department of Gynecology Oncology & Reproductive Medicine and Center for RNA
Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston,
Texas , USA
3 Sussex Health Outcomes Research and Education in Cancer (SHORE-C), Brighton and Sussex
Medical School, University of Sussex, Falmer, UK
4 Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
5 Charité Universitaetsmedizin Berlin Charité Campus Virchow-Klinikum, Berlin,
Germany
6 Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, California, USA
Correspondence to:
U.A.M.
ursula_matulonis@dfci.harvard.edu
Abstract
Ovarian cancer is not a single disease and can be subdivided into at least five different
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histological subtypes that have different identifiable risk factors, cells of origin, molecular
compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically
diagnosed at late stage, and has no effective screening strategy. Standard treatments for newly
diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent
cancer, chemotherapy, anti-angiogenic agents, and poly (ADP ribose) polymerase (PARP)
inhibitors are used and immunological therapies are currently being tested. High-grade serous
carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and is typically very
responsive to platinum-based chemotherapy at diagnosis. However, in addition to the other
histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy.
Consequently, understanding the mechanisms underlying platinum resistance and finding ways to
overcome them are active areas of study in ovarian cancer. Significant progress has been made in
identifying genes associated with high risk of ovarian cancer (such as BRCA1 and BRCA2) as
well as a precursor lesion of HGSC called a serous tubal intraepithelial carcinoma, which hold
promise for identifying individuals at high risk of developing the disease and for developing
prevention strategies.
Competing interests
U.A.M. has served as a consultant for AstraZeneca, ImmunoGen, Pfizer, Genentech, and Merck.
A.K.S., L.F., B.E.H., J.S. and B.Y.K. declare no competing interests.
Acknowledgements
U.A.M. has received research support from the Ovarian Cancer Research Foundation, Breast Cancer Research Foundation and Department of Defense A.S. has received research support from the National Institute of Health (CA109298, P50
CA083639, P50 CA098258)
Author contributions
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Introduction (U.A.M.); Epidemiology (J.S. and B.E.H.); Mechanisms/pathophysiology (A.K.S.,
B.E.H., U.A.M.); Diagnosis, screening and prevention (J.S., B.Y.K., and U.A.M.); Management
(U.A.M. and B.Y.K.); Quality of life (L.F.); Outlook (All authors); Overview of the Primer
(U.A.M.).
[H1] Introduction
Although once considered a single entity, ovarian cancer can be subdivided into different
histological subtypes that have different identifiable risk factors, cells of origin, molecular
compositions, clinical features and treatments. These histological subtypes include epithelial
cancers which account for ~90% of ovarian cancers and include serous, endometrioid, clear cell
and mucinous carcinomas (Figure 1, Table 1). Of these types, high grade serous carcinoma
(HGSC) is the most commonly diagnosed. Histologically and clinically, low-grade endometrioid
and low serous carcinomas are different compared to their high-grade counterparts; HGSC is
similar to high-grade endometrioid carcinomas (98, 100, 101). Other rarer histologies include
small cell carcinoma (aggressive cancers that predominantly occur in younger women with a
median age at diagnosis of 25 years of age) which have an uncertain tissue origin and
carcinosarcoma (also an aggressive cancer) (1, 2). Non-epithelial ovarian cancers, including germ
cell tumours and sex cord stromal tumors which account for approximately 10% of ovarian
cancers are not discussed in this Primer.
Some ovarian cancers originate from sites outside of the ovary; for example, many ovarian
HGSCs likely originate in the fallopian tube (3) and some subsets of ovarian cancer have been
shown to arise from the peritoneum (ref). Also, clear cell and endometrioid carcinomas can
originate from endometrial tissue located outside the uterus (endometriosis). On the basis of new
WHO classification, most of these types of ovarian cancer will now be reclassified as ‘ovarian or
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tubal cancers’ (4). Indeed, information regarding precursor sites of ovarian cancer has enabled
the investigation of new primary prevention strategies, such as risk-reducing and opportunistic
salpingectomy (surgical removal of the fallopian tube) (3). This increased understanding of the
biology underlying ovarian cancer has also translated to changes in clinical research; clinical
trials are now increasingly focusing eligibility requirements on the basis of ovarian cancer
histology.
Effective screening strategies for the early detection of ovarian cancer do not exist, but
individuals at high-risk of developing ovarian cancer, such as those with germline mutations in
BRCA1 or BRCA2 (encoding proteins involved in the repair of DNA damage via homologous
recombination) or other genes associated with high-risk of ovarian cancer, can be identified. For
these individuals, strategies to reduce ovarian cancer risk have been implemented through risk-
reducing surgery such as bilateral salpingo-oophorectomy (removal of the ovaries and fallopian
tubes). Screening strategies in women with average risk of developing ovarian cancer have
primarily focused on the biomarker CA125 (also known as mucin 16) and the use of transvaginal
ultrasonography. Combinations of these screening modalities have shown success in detecting
early stage cancers, but have not yet demonstrated definitive improvements in patient mortality
(6, 7).
The most active therapeutic agents against newly diagnosed ovarian cancer are platinum
analogues (either cisplatin or carboplatin), with the addition of a taxane (either paclitaxel or
docetaxel) (8-12). Treatment paradigms for first-line management of newly diagnosed ovarian
cancer include either primary surgical cytoreduction (to debulk tumours) followed by
combination platinum-based chemotherapy or neoadjuvant chemotherapy (NACT, administering
chemotherapy before surgery) followed by interval surgical cytoreduction and additional
chemotherapy after surgery. Recurrence of cancer after initial platinum-based chemotherapy is
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very common for women diagnosed with advanced cancer; is v the most difficult issue in the
treatment of cancer in these women is the eventual development of platinum resistance. Advances
in new therapeutics for recurrent ovarian cancer treatment include angiogenesis inhibitors, poly
(ADP ribose) polymerase (PARP) inhibitors (which block the repair of DNA damage) and
immunotherapy agents. Strategies using PARP inhibitors as part of the first-line treatment, as
well as combinations of these therapies for the treatment of both newly diagnosed and recurrent
ovarian cancer are underway. Overall, the treatment of ovarian cancer based on distinct genomic
makeup of the individual histological subtypes of ovarian cancer is evolving.
This Primer reviews the epidemiology and known risk factors associated with epithelial ovarian
cancer, in addition to the molecular biology, diagnostic and prevention approaches and
management of both newly diagnosed and recurrent cancer. This Primer also discusses patient
quality of life and concludes with examination of the future outlook for ovarian cancer, including
new prevention and screening approaches and promising new therapeutic advances.
[H1] Epidemiology
[H2] Incidence and mortality
Globally, 225,500 new cases of ovarian cancer are diagnosed each year, with 140,200 cancer-
specific deaths (13-15). Incidence and survival rates vary by country; Russian and the United
Kingdom have the highest worldwide rates while China has the lowest rates of ovarian cancer
(ref) . In the United States, approximately 22,280 new cases occur annually and the projected
number of deaths is 14,240 for 2016 (13). Interestingly, the annual incidence of ovarian cancer
reduced by 1.09% for women < 65 years of age and by 0.95% for women ≥65 years between
1998 and 2008 (ref), which might have been influenced by the changing pattern of hormonal
therapy prescriptions; reduced risk of ovarian cancer coincided with the announcement of causal
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association between ovarian cancer and use of hormonal replacement therapy and as such, fewer
prescriptions were written (37).
Over the past decade, minimal improvement in mortality has been observed (14, 15). The US
Surveillance, Epidemiology, and End Results database reports that overall survival for all patients
with ovarian cancer is 45.6%, but this varies greatly based on stage at initial diagnosis (16); 5-
year overall survival in patients with stage I cancer is 92.1% but is 25% for patients with stage III
and IV cancer (13, 16).
[H2] Risk factors
Several factors can increase the risk of developing ovarian cancer, including genetic factors, age,
post-menopausal hormonal therapy use, infertility and nulliparity.
[H3]Genetics. A range of genetic factors are associated with an increased risk of developing
ovarian cancer (Table 2). Germline BRCA1 and germline BRCA2 mutations are the most
significant known genetic risk factors for ovarian cancer and either mutation is found in up to
17% of patients (70, 71). Moreover, mutations in BRCA increases the risk of other cancers, such
as breast cancer, pancreatic cancer, prostate cancer and melanoma (BRCA2 only) and inheritance
of these genes have been extensively studied (17-19). Most subtypes of epithelial ovarian cancer
are associated with germline BRCA mutations, but HGSCs are the most common (17, 18) and
mucinous subtypes are rarely associated. Survival is improved for women with ovarian cancer
carrying germline BRCA mutations, compared with women who have ovarian cancer but are
wild-type for BRCA1 and BRCA2 (19). Germline BRCA2 mutations are associated with increased
overall survival, compared with germline BRCA1 mutations, likely because BRCA2 results in
enhanced platinum sensitivity and thus greater cancer cell killing compared with BRCA1 (19, 20).
Both the location of the BRCA mutation within the gene and the type of the mutation might also
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influence risk of developing ovarian cancer; the risk of developing breast cancer or ovarian
cancer, as well as the median age at diagnosis, can vary according to mutation type, nucleotide
position and the functional consequence of the mutation in patients with germline BRCA1 or
BRCA2 mutations (21).
Besides BRCA1 and BRCA2, other germline mutations in genes involved in DNA repair can
increase the risk of developing ovarian cancer, including genes that are part of the Fanconi
anaemia/BRCA pathway, such as RAD51C, RAD51D, BRIP1, BARD1, and PALB2 (18, 22-25;
Table 2). Inherited mutations in other genes involved in DNA repair, such as CHEK2, MRE11A,
RAD50, ATM and TP53, might also increase the risk of developing ovarian cancer (18, 22, 23).
Other inherited disorders, such as Lynch syndrome, can increase the risk of ovarian cancer.
Lynch syndrome is associated with colorectal, endometrial and ovarian cancers, but can also be
associated with cancers of the urinary tract, stomach, small intestine and biliary tract. The
syndrome is characterized by inheritance of a germline mutation in genes of the DNA mismatch
repair system, namely, MLH1, PMS2, MSH2, or MSH6, which are mutated in differing
frequencies (26-28). Patients with Lynch syndrome-associated ovarian cancer have a mean age at
presentation of 48 years (compared with a median age of ~68 years in those without Lynch
syndrome), with approximately 50% of patients having stage I cancer. Additionally, endometrioid
and clear cell carcinomas are more common in patients with Lynch syndrome than would be
predicted for sporadic ovarian cancer (26). Even though both BRCA and the DNA mismatch
repair pathways are involved in DNA repair, the specific mechanisms are not known why cancers
arise in specific organs associated with these inherited mutated genes.
[H3] Oral contraceptives and hormone replacement therapy. The use of oral contraceptives
has been shown to reduce the risk of developing ovarian cancer in individuals with a germline
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BRCA1 mutation, as well as in those without a genetic predisposition (30, 31). One meta-analysis
showed a lifetime reduction of 0.54% of ovarian cancer with the use of oral contraceptives for an
average of 5 years (31) (ref). Interestingly, an analysis from the Ovarian Cancer Cohort
Consortium (including data from 21 studies, encompassing 1.3 million women and 5,584 ovarian
cancers) showed that oral contraceptive use was associated with reduction in serous,
endometrioid and clear cell carcinomas, but not mucinous carcinomas (ref). The relative
oestrogen and progestin doses in oral contraceptives does not affect the incidence of
ovarian cancer, but longer duration of oral contraceptive use is associated with reduced
risk (32). However, other meta-analyses have found insufficient evidence to recommend either
for or against the use of oral contraceptives to prevent ovarian cancer, given their potential harm
from adverse vascular events and minimal increase in other cancers (such as breast cancer)
weighed against the potential for ovarian cancer risk reduction (32).
Hormone replacement therapy has been shown to increase the risk of developing ovarian cancer
in post-menopausal women; oestrogen-only therapy increased risk by 22% and the combined
oestrogen and progesterone therapy increased risk by 10% (33-35). However, a meta-analysis
showed a similar increase in the risk of developing ovarian cancer, specifically, serous and
endometrioid carcinomas, in menopausal women using hormone replacement therapy, regardless
of whether the therapy contained only oestrogen or a combination of oestrogen and progesterone
(36). Others have confirmed this finding but have also shown a reduced risk of clear cell cancer in
women using hormone replacement therapy (Wentzensen et al JCO 2016). Interestingly, in
women diagnosed with ovarian cancer and who also have severe menopausal symptoms, the use
of hormone replacement therapy appears safe and has no effect on overall survival (38). Thus, use
of hormone replacement therapy can be considered if patients are having significant menopausal
symptoms (38).
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[H3] Reproductive factors. Retrospective studies have identified several other factors that can
influence the risk of ovarian cancer such as parity, prior tubal ligation, salpingectomy and
unilateral or bilateral oophorectomy (surgical removal of the ovary) (29, 42,43). Women who
have given birth have a reduced risk of all subtypes of ovarian cancer, with the strongest risk
reduction noted for clear cell cancers, compared with women who have not given birth. Unilateral
oophorectomy is associated with a 30% reduction in the risk of ovarian cancer, which is not
histological subtype-specific. Bilateral oophorectomy is also effective in reducing risk of ovarian
cancer in women with a genetic predisposition . Interestingly, 0% of women with a BRCA2
mutation and 1.1% with a BRCA1 mutation developed a primary peritoneal carcinoma following
bilateral oophorectomy (ref). (42). Tubal ligation and hysterectomy are also associated with a
reduction in the risk of developing ovarian cancer; tubal ligation is associated with reduction in
risk of clear cell and endometrioid carcinomas and hysterectomy is associated with reduction in
risk of clear cell carcinoma (Wentzensen et al) (29, 42, 43).In one study, reproductive risk factors
such as tubal ligation, parity of ≥2, endometriosis and younger age were more strongly associated
with development of dominant ovarian tumors (meaning one ovarian tumour is at least twice as
large as the tumour on the other ovary), than with non-dominant cancers which are thought to
arise in the fallopian tube and are mostly HGSC (44). Also, endometriosis has been associated
with endometrioid and clear cell ovarian cancer as well as low grade cancers (Wentzensen et al).
In women with germline BRCA mutations, tubal ligation and breastfeeding have similarly been
identified as a risk factor associated with a decreased risk of ovarian cancer (29).
[H3] Lifestyle factors. Several studies have identified obesity as a possible risk factor for the
development of postmenopausal ovarian cancer; one meta-analysis showed an approximate 13%
increase in risk of ovarian cancer in postmenopausal women with a 5kg weight gain, who did not
use, or had low use of hormone replacement therapy (45). Moreover, obesity is associated with an
elevated risk of endometrioid and mucinous carcinomas but not HGSC (ref). However,
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conflicting data have been reported in other studies (Wentzensen et al). Obesity is also a risk for
poor outcomes following diagnosis of ovarian cancer; women with obesity and low grade serous
carcinoma (LGSC), HGSC or endometrioid carcinoma have a worse outcome compared with
non-obese women (47). Meta-analyses have suggested a beneficial effect of regular physical
activity on the risk of ovarian cancer, with a 30–60% reduction in risk in the most active women
(46).
Several studies have examined the association between dietary factors and the risk of developing
ovarian cancer in the general population. Levels of milk consumption do not confer a significant
risk for developing ovarian cancer, but one study noted a trend suggesting an inverse association
between intake of skim milk and lactose in adulthood and risk (49). Moreover, this study showed
an inverse relationship between lactose intake and the risk of endometrioid carcinoma (49).
Studies have also assessed the association between other dietary factors, including vitamins and
flavonoids and risk of ovarian cancer. The intake of folate or vitamins A, C, or E during
adulthood, or intake of a specific diet (defined by dietary scores) does not alter the risk of ovarian
cancer (53, 54). Interestingly, flavonoids and black tea might be associated with a reduced risk of
ovarian cancer, but these require further study (55).
Other lifestyle factors that might affect the risk of ovarian cancer include the use of talc powder
(reviewed in 52), medications such as NSAIDS and smoking. With respect to talc powder, results
from case control and prospective studies have been variable; one study showed a modest
increase in the risk of ovarian cancer, but other studies have shown no increase in risk with talc
use (50, 51). Aspirin use was associated with a reduced risk of developing ovarian cancer,
especially among women who took daily, low-dose aspirin, regardless of their age; the same
associations were not shown for acetaminophen (56). Regular aspirin use was associated with
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reduced risks of endometrioid and mucinous carcinomas and a significance reduction in
risk of serous carcinomas. However, no prospective trials testing aspirin for ovarian cancer risk
reduction have been conducted. Non-aspirin NSAID use was associated with a trend to suggest a
lower risk of ovarian cancer (56), specifically, of serous carcinomas. Cigarette smoking was
associated with a significantly lower risk of clear cell carcinoma but an increased risk of
mucinous carcinoma (Wentzensen et al).
Finally, data from the Nurse’s Health Study show that persistent depression – defined as
meeting the definition of depression based on current and past questionnaires – might
increase the risk of ovarian cancer compared with women who do not exhibit depressive
symptoms (48)
[H1]Mechanisms/pathophysiology
The Cancer Genome Atlas (TCGA) project, along with other projects that catalogue genetic
mutations associated with cancer have produced important molecular data of the different
histological subtypes of epithelial ovarian cancer (63, 65, 66). These data, in turn, open the
pathway to improved therapeutic, early detection and risk-reducing strategies. The recognition
that ovarian cancer is comprised of histologically and molecularly distinct subtypes has
influenced clinical trial design strategies and patient eligibility and has led to rational clinical
management (Table 2) (67, 68).
[H2] Molecular alterations
The best-studied genetic alterations in ovarian cancers are those involved in DNA repair (Figure
3). Germline or somatic mutations in homologous recombination genes have been identified in
approximately one third of ovarian carcinomas, including both serous and non-serous histologies
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and subtypes that were not previously believed to have characteristics of homologous
recombination deficiency (clear cell and endometrioid carcinoma, in addition to carcinosarcoma).
As mentioned previously, the commonly implicated inherited genes are BRCA1, BRCA2,
BRIP1, genes that are part of the Fanconi anaemia pathway (RAD51C, RAD51D, BRIP1,
PALB2 and BARD1) and genes involved in DNA mismatch repair (MSH2, MLH1, PMS2
and MSH6).
Despite genomic data showing recurrent mutations in patients with ovarian cancer, some tumours,
particularly the HGSC subtype, are genetically heterogeneous (63, 66, 76), reflecting the
underlying genomic complexity of this disease. For example, one study demonstrated intratumor
genomic heterogeneity in patients with newly diagnosed HGSC (76).
[H3] HGSC. HGSC has been extensively characterized both at initial diagnosis of ovarian cancer
as well as at disease recurrence after exposure to platinum-based chemotherapy (63, 66).
TP53 is the most commonly mutated gene in HGSC (63, 66). TP53 mutations can be in-frame
and frameshift insertions and deletions, as well as missense or nonsense mutations (69). TP53
mutations frequently occur in the region of the gene encoding the DNA binding domain, but can
also occur in regions encoding the non-DNA binding domains. Tumours lacking TP53 mutations
have signs of p53 dysfunction through a copy number gain of MDM2 or MDM4, the gene
products of which are involved in the regulation and degradation of p53 (69).
Genomic analyses have revealed defects in homologous recombination in approximately 50% of
analysed HGSCs (70, 71). Defective homologous recombination is associated with both germline
and somatic BRCA mutations, as well as alterations in other DNA repair pathway genes (Figure
3) (63). BRCA1 is critical for DNA repair, cell-cycle checkpoint control, mitosis, remodeling of
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chromatin, and transcriptional regulation; BRCA2 is important in homologous recombination and
DNA repair (72). Hypermethylation of the BRCA1 promoter has also been shown in a substantial
subset of HGSCs but does not influence overall survival and outcome (63).
Additional recurrent molecular alterations identified in HGSC include defective Notch,
phosphoinositide 3-kinase (PI3K), RAS/MEK and FOXM1 pathway signalling, as well as a high
level of somatic copy number alterations in the genes encoding proteins in these pathways (63).
Other mutated genes that play a part in the pathogenesis of HGSC and that could also serve as
potential therapeutic targets for ovarian cancer include AURKA, ERBB3, CDK2, MTOR, BRD4,
and MYC (63, 77, 78). For example, one study showed that activity of the epigenetic transcription
modulator, bromodomain-containing protein 4 (encoded by BRD4) is required for the
proliferation and survival of HGSC cell lines (77). Also, ovarian cancer cells sensitive to BRD4
inhibition have high expression of MYC, another important gene found altered in HGSC (77).
HGSC has been further subdivided using data from gene expression profiling (79, 80). TCGA
identified 4 subtypes of HGSC based on gene expression: differentiated, immunoreactive,
mesenchymal and proliferative subtypes, which have differences in clinical outcome, although
this has not been clinically useful for patient management (79-81). Attempts to more narrowly
define the subgroups of HGSC have included integrated genomic analyses incorporating multiple
platforms. For example, a micro RNA (miRNA)-regulated network was identified that is
associated with the mesenchymal subtype of HGSC and with poor clinical outcomes (82). Some
studies have used gene expression profiling to predict the prognosis of patients with advanced-
stage HGSC, in addition to treatment resistance and response to platinum-based chemotherapy
and PARP inhibitors. However, these studies relied on retrospective analyses and prospective
data from randomized trials are still needed to show usefulness of expression assays in subtyping
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patients (83).
The level of molecular diversity of HGSC at the time of diagnosis, its evolution, change over
time, the presence of few druggable driver mutations and the high rate of copy number alterations
in genes of multiple signalling pathways characterizes the genomic complexity of this cancer.
Indeed, this molecular complexity provides insight into perhaps why the development of effective
therapies for HGSC has been difficult to achieve (63, 66).
[H3] Other epithelial subtypes. The genomic landscapes of other histological subtypes of
ovarian cancer have also been studied. Clear cell carcinomas are complex at the genomic level
and can have mutations in ARID1A, PIK3CA and PTEN (94). BRAF and KRAS mutations are
common in LGSC (95, 96). Also, LGSC mostly exhibits mutational stability such that the extent
of tumour genetic evolution is low in this cancer type in each patient, but these tumours are
typically more unresponsive to chemotherapy compared to HGSC (97).
Endometrioid adenocarcinomas frequently carry mutations in PTEN, PIK3CA, and CTNNB1 (98).
Ovarian cancers associated with endometriosis, such as clear cell and endometrioid carcinomas,
are associated with ARID1A mutations (98, 99). Low grade endometrioid carcinomas can carry
loss of PTEN and mutations in PIK3CA and KRAS (98, 100).
Mucinous carcinomas can carry KRAS mutations (102). C>T transitions in an NpCpG
trinucleotide context have been shown to be the predominant mutational signature of mucinous
carcinomas, indicating deamination of methylcytosines (103). Approximately half of mucinous
carcinomas have mutations in TP53 , with other frequent mutations occurring in KRAS,
BRAF,CDKN2A, RNF43, ELF3, GNAS, ERBB3 and KLF5 (103).
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Hypercalcaemia-associated small cell carcinomas are associated somatic or germline mutations in
SMARCA4 (1, 104).
[H2] Precursor lesions
The distal fallopian tube has been identified as a precursor site of HGSC in a substantial
proportion of patients due to the presence of atypical tubal epithelial cells in women with BRCA1
or BRCA2 mutations. This site was identified with the discovery of serous tubal intraepithelial
carcinoma (STIC) — an early lesion — during risk-reducing bilateral salpingo-oophorectomy in
these women, with the presence of STICs in the fallopian tubes of women with advanced-stage
ovarian cancer and with identification of precursors in the fallopian tube characterized by DNA
damage and mutations in TP53 (3, 59-61, 87, 88, 91). STIC can be identified in 18–60% of cases
of advanced-stage HGSC (3, 59, 60, 86-88) and up to 80% of early stage HGSC. However, STICs
are not found in all patients with HGSC and alternative pathways for the pathogenesis of HGSC
likely exist (89). One study proposed a dualistic model for HGSC pathogenesis that incorporates
the variables of the patient (for example, presence of STIC, BRCA status, patient age and
morphological features of the HGSC) (91). The study suggested two pathways of HGSC
development based on differences in STIC frequency, tumour morphology and outcome, known
as classic or SET (>50% solid, pseudoendometrioid, or transitional) pathways. The classic
pathway involves the presence of a STIC precursor and a longer timeframe from STIC to
development of HGSC. Conversely, the SET pathway typically occurs in younger women, who
have a lower STIC frequency and higher level of responsiveness to chemotherapy and PARP
inhibitors. The two pathways of HGSC development might have implications for the potential
ineffectiveness of risk reducing bilateral salpingo-oophorectomy for some high-risk patients.
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[H2] Immune system and tumour microenvironment
Another developing field of research in ovarian cancer pathogenesis is the role of the immune
system and the tumor microenvironment. Cytotoxic T -cell infiltration in ovarian cancer has been
shown to correlate with improvement in overall survival in several studies (106, 107). For
example, antitumor immune responses composed of tumor-reactive T cells and tumour-specific
antibodies that can be detected in peripheral blood, ovarian cancer tissue and ascites (108-111).
Furthermore, cytotoxic T cell infiltration in ovarian tumours correlates with improvement in
overall survival as shown by several groups (106, 107).
Within the many components of the tumor microenvironment, angiogenesis has a critical role in
the pathogenesis of epithelial ovarian cancer, promoting tumour growth and metastasis (112).
Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic factors
identified in ovarian cancer, with other proangiogenic factors including fibroblast growth factor,
angiopoietins, endothelins, IL-8, IL-6, macrophage chemotactic proteins and platelet-derived
growth factors also identified (113, 114).
[H2] Chemotherapy-resistance
HGSC and other high-grade ovarian cancer histologies, for example high-grade endometrioid
carcinoma, can be further analysed on the basis of platinum sensitivity. Platinum-sensitive
ovarian cancers are defined as having a platinum-free interval (PFI; time elapsed between the last
dose of platinum-based chemotherapy and evidence of cancer progression) of 6 months or
greater, whereas platinum resistant cancers have a PFI of <6 months. In patients with HGSC, one
study showed that inactivation of genes by disruption of transcriptional units (gene breakage) can
inactivate the tumor suppressors RB1, NF1, RAD51B and PTEN, which likely contributes to
increasing chemotherapy and platinum resistance (66). Upregulation of the ABCB1 gene
encoding for the drug efflux pump multidrug resistance protein 1 (MDR1) leading to MDR1
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overexpression could also explain mechanisms of platinum ressitance. Also, germline or somatic
mutations in BRCA1 or BRCA2 could lead to a favorable treatment response with improved
responsiveness to chemotherapy (18, 63). Amplification of the 19q12 locus which involves
CCNE1, (encoding G1/S-specific cyclin-E1, also known as cyclin-E1, which is a cell cycle
regulator) was associated with primary platinum-resistant and refractory ovarian cancers (66);
this leads to abundance of cyclin E1, which subsequently activates transcription of BRCA1 and
BRCA2 , elevating levels of the BRCA proteins and leading to platinum-resistance (63).
[H1]Diagnosis, screening and prevention
[H2] Diagnosis
[H3] Clinical presentation. Most women with ovarian cancer are diagnosed in later life, with a
median age of diagnosis of 63 years (16). Most women are symptomatic at disease presentation
and have ascites (fluid in the peritoneal cavity) and gastrointestinal dysfunction (for example
constipation and/or bowel obstruction). Other symptoms at initial presentation include abdominal
bloating, abdominal and/or pelvic pain, fatigue, gastrointestinal dysfunction (such as nausea and
vomiting, constipation, diarrhoea and gastrointestinal reflux) and shortness of breath (5).
Respiratory symptoms can result from extensive intra-abdominal cancer with ascites, causing
diaphragmatic pressure, pleural effusions and/or a pulmonary embolus.
Symptoms of ovarian cancer might be initially missed or attributed to other disease processes
because they are general and non-specific. Accordingly, diagnosis frequently occurs when the
cancer has reached a late stage (either stage III or IV), because symptoms have become apparent
and require intervention (5), and/or the symptoms are more-severe, indicative of extensive
peritoneal carcinomatosis (cancer of the peritoneum), ascites, and the possible bowel involvement
of cancer. The combination of abdominal bloating, increased abdominal size and urinary
symptoms has been found in 43% of patients with an eventual diagnosis of ovarian cancer but
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only in 8% of patients not diagnosed with ovarian cancer (115). Women presenting with severe or
frequent symptoms and those of recent onset warrant further diagnostic investigation because of
the association of these symptoms with ovarian masses (155).
Importantly, these symptoms — and their late presentation — largely apply to those with HGSC.
By contrast, histologies such as clear cell and small cell carcinoma can become symptomatic at an
earlier stage. For example, hypercalcaemia can be the initial presentation of clear cell or small
cell carcinomas. These tumour types are also associated with many of the same symptoms
observed with more advanced HGSC, such as abdominal distension, pelvic pressure and/or pain,
as well as pressure of the ovarian mass on the bowel or urinary tract system. Most patients with
clear cell carcinomas present at an early stage and might present with symptoms related to pelvic
pressure.
[H3] Diagnostic work up. In patients with indicative symptoms diagnostic work up includes
physical examination of the patient, consisting of pelvic examination and recto-vaginal
examination, in addition to radiographic imaging (transvaginal ultrasonography, abdominal
ultrasonography, CT, MRI and/or PET (Figure 2)). The CA125 blood test can also be used in
combination with other diagnostic tests for the detection of ovarian cancer. Laparoscopic surgery
with removal of the mass is recommended (116) and will also give further information on the
tumor histology. Results from diagnostic testing, especially transvaginal ultrasonography, can
give information regarding the ovarian mass such as size, location and level of mass complexity,
which can help clinicians determine the level of suspicion for cancer (ref). More advanced cancer
is associated with ascites and peritoneal carcinomatosis within the abdominal cavity; in order to
confirm a diagnosis of ovarian cancer, a tissue biopsy must be performed.
19
[H3] Staging. Pathological evaluation and tumour staging of ovarian cancer is based on surgical
assessment of the cancer at initial diagnosis, including removal of lymph nodes, tissue biopsy and
abdominal fluid and uses the International Federation of Gynecology and Obstetrics (FIGO)
staging system (Table 3). The staging system has recently changed with acceptance of the
common, Müllerian-derived multicentric origin of ovarian, fallopian tube and peritoneal cancers
and that these cancers should be grouped using one system (127). The latest FIGO staging system
has three other notable characteristics: stage IC tumours have been subdivided based on the
mechanism underlying rupture of the ovarian capsule and the presence of malignant ascites (the
presence of tumour cells in ascites), stage IIC has been eliminated and stage III has a clearer
definition that encompasses the size of metastases as well as the presence of metastases to the
lymph nodes. Moreover, stage III was reclassified to account for differences in the clinical
outcomes in patients with metastases to the lymph nodes who do not have peritoneal
carcinomatosis, versus patients with peritoneal carcinomatosis (128, 129). Additionally, stage IV
has been further divided into stage IVA, and IVB. The FIGO staging system recommends that the
primary tumour site (the ovary, fallopian tube or peritoneum) and the histological grade be stated
in either the operative report and/or the final pathology report (127).
Surgical staging of ovarian cancer by gynaecological oncologists has been shown to be superior
to that performed by non-oncological (general) surgeons as have patient outcomes (138–140).
Indeed the issue with accurate staging is pertinent; one study found that only 54% of women with
ovarian cancer received correct staging as determined by a gynecologic oncologist (141). When
patients are operated by non-gynecologic oncologists, such as general surgeons or general
gynecologists, the diaphragm was not visualized in 86% of cases and the omentum was not
biopsied in 68% of cases (141), meaning cancer was commonly missed in the diaphragm, pelvic
peritoneum, peritoneal fluid and omentum.
20
[H2]Screening
No current screening strategy has affected survival of patients with ovarian cancer. Creation of a
successful screening strategy for ovarian cancer is challenging because this is not a common
disease and includes a range of histological subtypes, each with different biological and clinical
properties. For example, patients with LGSC have substantially better overall prognoses than
patients with more-aggressive, high grade cancers and might require a different screening strategy
(95).
The CA125 blood test is not an effective screening test when used alone, given that CA125 is
only elevated in 50% of stage I ovarian cancers and can also be increased in benign disorders
such as uterine fibroids, ovarian cysts and other conditions such as liver disease and infections
(117, 118). CA125 elevation is most frequently observed in HGSC, with lower levels of CA125
in other non-serous subtypes (ref).
Combining the CA125 blood test and radiographic imaging, such as transvaginal
ultrasonography, has been evaluated for use as a screening strategy. One of the largest studies to
examine this combination was the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer
Screening Randomized Controlled Trial (120), which enrolled 78,216 women between the ages of
55–74 years. Women were randomly assigned into two groups of approximately equal size, to
receive either annual screening (encompassing yearly CA125 tests for 6 years and transvaginal
ultrasonography for 4 years) or usual care (no yearly CA125 or transvaginal ultrasound, but could
have undergone bimanual examination with ovarian palpation). Ovarian cancer was diagnosed in
212 women (5.7 per 10,000 person-years) in the screening group and in 176 women (4.7 per
10,000 person-years) in the usual care group (rate ratio 1.21; 95% CI=0.99–1.48) (5) and the
stage distributions of cancer were similar for the two groups (stage III and IV cancers comprised
almost 80% of cancers in both groups). Also, no significant reduction in overall mortality was
21
observed with screening (3.1 deaths per 10,000 women in the screened group and 2.6 deaths per
10,000 person-years in the usual care group; mortality rate ratio of 1.18 (95% CI= 0.82–1.71)) (5)
Although the CA125 tested alone as a screening marker has been deemed ineffective, the UK
Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) study evaluated the strategy of
longitudinal measurements of CA125 levels has also been assessed for screening of ovarian
cancer, in an algorithm termed ‘risk of ovarian cancer algorithm’ (ROCA) (5, 7,123). In one arm
of this study, ROCA was the primary screening modality with transvaginal ultrasonography used
as a secondary screening measure based on CA125 levels (7). The ROCA algorithm interpreted
longitudinal CA125 data and triaged women to either normal (annual screening), intermediate
(repeat CA125 testing in 3 months) and elevated risk (repeat CA125 testing and transvaginal
ultrasonography in 6 weeks). Annual screening used transvaginal ultrasonography as the primary
test, following which, patients were subdivided into 3 groups based on ultrasonography results;
normal (annual screening), unsatisfactory (repeat in 3 months) and abnormal (scan with a senior
ultrasonographer within 6 weeks). In this study, 202,638 women were randomly assigned into one
of three groups (screening based on the ROCA algorithm, ultrasonography alone and no
screening) (7) and followed-up for a median period of 11.1 years. The proportion of women
diagnosed with ovarian cancer was similar between groups (between 0.6–0.7%), but lower stages
(stage I-IIIA) of disease was in a higher proportion of patients in the ROCA screened group than
in those who were not screened (P <0.0001). However, there was no difference between patients
in the ROCA group and those who received transvaginal ultrasonography (P=0.57). Mortality
reduction was not significant between any of groups, therefore, the ROCA test cannot currently
be recommended as a screening strategy for ovarian cancer; further follow-up of this study is
necessary to understand the long-term potential of this screening strategy.
WAP four-disulfide core domain protein 2 (also known as human epididymis protein 4 (HE4))
22
has also been tested as a potential biomarker for use in ovarian cancer screening (124). A
systematic review reported better sensitivity, specificity and likelihood ratios for HE4 compared
with CA125, but this has not yet been analysed within a screening strategy (125). The use of
other novel markers for ovarian cancer screening are under investigation, including, for example,
DNA analysis of uterine lavages or Pap smears for TP53 mutations (126).
[H2] Prevention
Salpingectomy has gained favour as a prevention technique based on the presence of precursor
lesions in the fallopian tubes of some women with ovarian cancer as discussed above. However,
no randomized prospective studies have been performed to determine the benefit or evidence of
risk reduction following salpingectomy (39-41).
The Society of Gynecologic Oncology guidelines and recommendations for the prevention of
ovarian cancer. These guidelines, in addition to others, recommend all women with invasive
ovarian cancer (regardless of family history, histology or age) should undergo genetic testing and
genetic counseling. The purpose of this testing is to assess women for the presence of a high risk
gene which could convey increased risk for both the individual and family members, as well as
having implications for outcome and therapeutic management (57, 58). Moreover, the Society of
Gynecologic Oncology guidelines recommend performing risk-reducing bilateral salpingo-
oophorectomy in women aged 35–40 years who are at increased genetic risk (the presence of
germline mutations in high risk genes) of developing ovarian cancer, as well as individualizing
the age at which women undergo risk-reducing surgery (57). Also, the Society of Gynecologic
Oncology guidelines mandate and recommend microscopic examination of the entire ovary and
fallopian tube following risk-reducing bilateral salpingo-oophorectomy in high-risk women, to
rule out early invasive cancers (57, 59-61).
23
The annual risk of ovarian cancer in individuals of specific age groups with germline BRCA
mutations and intact ovaries has been estimated, to help guide clinicians and patients about
appropriate timing of the risk-reducing bilateral salpingo-oophorectomy (62). In one study, risk-
reducing salpingo-oophorectomy reduced risk of ovarian cancer in women with BRCA mutations
by 80%. Timing of risk-reducing bilateral salpingo-oophorectomy is important, as performing
surgery in women < 45 years of age has been associated with an increased risk of cardiovascular
disease, osteoporosis and osteopenia (57); oestrogen replacement should be considered in these
patients (if they have not had breast cancer), but the benefits and potential risks or optimal
duration of oestrogen therapy has not been determined (57).
Variants of unknown importance occur in BRCA1 and BRCA2, as well as other high risk genes
implicated in ovarian cancer, but the effects of these variants on ovarian tumorigenesis are
currently unknown (75). Variants of unknown importance represent dilemmas for women who
are diagnosed with them, as these variants carry an unknown cancer risk, meaning patients and
their family members cannot be accurately counseled about risk reduction and preventative
surgeries.
[H1]Management
At initial diagnosis, patients are faced with the challenge of accessing appropriate medical
treatment and quickly making complex decisions about their care. The choice of physician can
impact outcomes (130, 131) as can adherence to the guidelines for the standard of care (132,
133); surgery performed by a gynecologic oncologist results in superior outcomes and survival,
compared with surgery performed by a non-gynecologic oncologist, such as a general surgeon.
The primary aim of treatment for ovarian cancer is to maximize cancer control and to palliate
disease symptoms for as long as possible. Surgery performed by a gynecologic oncologist is the
main treatment for most patients with ovarian cancer. The extent of surgery is determined by the
24
stage of cancer and patient factors; for example, women with more advanced cancer might
undergo bilateral oophorectomy, but women with low risk, stage I cancer (such as mucinous
histologies) and young women who wish to preserve fertility, might undergo unilateral
oophorectomy of the affected ovary only. Surgical cytoreduction results are frequently referred to
as suboptimal (meaning any focus is ≥1cm in size, R2 resection), optimal (meaning <1 cm
residual cancer, R1 resection) or no evidence of residual macroscopic disease (R0 resection).
New studies only define optimal surgical results if macroscopic complete resection of the cancer
has been achieved. Patients with macroscopic complete resection (R0) following surgery have
significant improvements in outcomes, such as overall survival and progression-free survival
(PFS), compared with patients with remaining post-operative visible disease (135, 136). For
example, in one study (GOG 182) patients with stage III or IV ovarian cancer with optimal
cytoreduction had a worse prognosis than patients with no evidence of residual macroscopic
disease or R0 followed by platinum-based chemotherapy. Nevertheless, patients with optimal
cytoreduction have a significantly better median PFS and overall survival than patients with
suboptimal cytoreduction (134-136).
[H2]Newly diagnosed ovarian cancer
[H3] Primary surgery. The primary treatment for women with newly diagnosed ovarian cancer
is primary surgical cytoreduction (Figure 4). The primary goal of surgery is to achieve
macroscopic complete resection of disseminated carcinomatosis, often involving complex
surgical techniques, including en bloc resection of the bowel, uterus and adnexal masses, as well
as peritonectomy. In some cases, colonoscopy and/or upper endoscopy might be required, to rule
out the possibility of a primary gastrointestinal cancer, rather than a primary ovarian cancer.
Systematic pelvic and paraaortic lymph node dissection is also necessary in patients with high-
risk early stage ovarian cancer, or patients with stage II and IIIA disease, because nodal
metastases signify a higher stage of disease, poorer prognosis and the need for different treatment
25
strategies.
It is critical for the surgeon to define the best surgical approach and determine the appropriateness
of surgery prior to administration of chemotherapy versus NACT. If NACT is to be administered,
a biopsy is needed to confirm pathology consistent with an ovarian, tubal or peritoneal primary
cancer, before chemotherapy can be commenced.
[H3] Adjuvant chemotherapy. Recommendations for the use of adjuvant chemotherapy using
platinum-based chemotherapy for patients with early stage ovarian cancer depend on cancer
stage, grade and histology. Many patients with grade I, stage I cancer are not treated with
chemotherapy post-surgery but those with higher grades (≥ grade II) and/or specific histologies
(such as HGSC and clear cell carcinomas) undergo adjuvant systemic platinum-based
chemotherapy (142). Indeed, several first-line adjuvant systemic chemotherapy strategies have
led to an improvement in overall survival for patients with newly diagnosed, advanced-stage
ovarian cancer including the addition of paclitaxel to platinum-based chemotherapy agents, use of
intraperitoneal cisplatin in patients with optimally cytoreduced cancer and incorporation of dose-
dense weekly paclitaxel treatment instead of administration every 3 weeks (7, 143-145).
Studies have examined the efficacy of different combinatorial treatments to optimize adjuvant
chemotherapy, including combinations of platinum-based chemotherapy agents (cisplatin and
carboplatin), taxanes (paclitaxel, docetaxel), anti-angiogenic agents (bevacizumab, nintedanib,
trebananib and pazopanib) and other drugs (pegylated liposomal doxorubicin, gemcitabine)
(Table 4).
In 2011, the European Medicines Agency (EMA) approved the use of bevacizumab as an addition
to carboplatin/paclitaxel chemotherapy and maintenance therapy in patients with newly
diagnosed, advanced-stage ovarian cancer, based on the improvement in PFS in the GOG218 and
ICON7 studies (Table 4). A retrospective analysis of the ICON7 study of patients with
26
suboptimally cytoreduced stage IIIC or stage IV cancer showed an overall survival benefit with
the addition of bevacizumab to a carboplatin/paclitaxel backbone, but no improvement in overall
survival was observed in the intent to treat population of patients entered in either ICON7 or
GOG 218 (151-153). Despite being available in Europe, bevacizumab has not been approved for
patients in the United States, making collaborative trial design for both newly diagnosed and
recurrent ovarian cancer challenging.
[H3] Neoadjuvant chemotherapy. NACT consisting of carboplatin and paclitaxel for 3 cycles is
then followed by interval (meaning between rounds of chemotherapy) surgical cytoreduction and
additional chemotherapy post-surgery for a total of 6 cycles of chemotherapy. NACT is a possible
treatment alternative to upfront surgical cytoreduction for ovarian cancer, especially for patients
who are too ill for initial surgery or if the cancer burden is too extensive to allow macroscopic
complete resection. Two trials have demonstrated comparable outcomes for first-line surgery with
adjuvant chemotherapy, compared with NACT followed by surgery and post-operative
chemotherapy, with less morbidity and mortality but similar outcomes in PFS and overall survival
in the group that received NACT (160, 161). Data from the first study showed NACT followed by
interval cytoreductive surgery is not inferior to primary cytoreductive surgery followed by
chemotherapy and no significant difference in PFS (12 months) or overall survival (29–30
months) was found between groups (160). The second study (CHORUS) in patients with
advanced stage III or IV cancer randomly assigned to either primary cytoreductive surgery
followed by chemotherapy (consisting of either carboplatin and paclitaxel or carboplatin alone),
or to NACT (3 cycles), followed by cytoreductive surgery and three more cycles of chemotherapy
(carboplatin and paclitaxel or carboplatin alone) showed a non-significant difference in overall
survival between the group that received NACT (24.1 months) and those that received upfront
surgery (22.6 months; 95% HR 0.87, 95% CI 0.72–1.05) (161). Additionally, PFS was similar for
both groups; 12.0 months in the NACT group, compared with 10.7 months for the primary
27
surgery group (HR 0.91, 95%CI: 0.76–1.09). However, the number of post-operative deaths was
lower in the NACT group compared to the upfront surgery group (161).
Some medical centres are testing the use of surgical algorithms with diagnostic laparoscopy to
determine tumour resectability, to identify patients who are appropriate for first-line
cytoreductive surgery, versus those suitable for NACT, but no validated preoperative instrument
has currently been established (162). Controversy persists over the identification of the most
appropriate candidates for NACT and whether NACT induces upfront platinum resistance.
Accordingly, a general consensus regarding the equivalence of NACT followed by surgery and
upfront surgery followed by adjuvant chemotherapy is lacking (163). Also, some groups have
argued that the overall survival and PFS outcomes used in the aforementioned randomized trials
of NACT versus upfront surgical cytoreduction (160, 161) are inferior to other trials and that
inferior complete resection rates were observed in the primary surgery control group, particularly
in the CHORUS study (164, 161).
[H3] Maintenance therapy following NACT. Aims of maintenance therapy are to prolong a
clinically meaningful survival endpoint, such as PFS and also preserve a patient’s quality of life.
The use of maintenance therapy following platinum-based chemotherapy has been investigated
and reviewed (165, 166). Monthly paclitaxel treatment (for a duration of either 3 months or 12
months) has been assessed in patients with ovarian cancer following completion of NACT (167);
no benefit in overall survival was observed with 12 month paclitaxel treatment, compared to
treatment for 3 months, but PFS was longer in the 12-month versus 3-month groups. However,
due to the risk of developing adverse effects with continuation of monthly paclitaxel for 12
months (for example, alopecia and peripheral neuropathy), the use of paclitaxel for maintenance
28
therapy after platinum-based chemotherapy is not commonly used; currently, the standard of care
following completion of platinum-based chemotherapy is observation alone (142).
Pazopanib has also been studied for use in maintenance therapy, resulting in an increase in PFS,
but no improvement in overall survival (156). Pazopanib is also associated with a significant
toxicity profile such as fatigue, gastrointestinal toxicities (such as nausea and/or diarrhoea),
hypertension and myelosuppression (156).
Bevacizumab is approved in Europe as maintenance therapy following initial
platinum/taxane/bevacizumab chemotherapy based on GOG218 and ICON7 results.
[H2]Recurrent disease
[H3] Monitoring for recurrence
>80% patients with advanced-stage ovarian cancer will experience recurrence of their primary
cancer. Recurrent ovarian cancer is generally incurable, but rare exceptions to this exist, such as
patients with isolated metastatic cancer in whom the disease can be fully resected after secondary
cytoreductive surgery or treatment with localized radiotherapy.
Many patients with recurrent ovarian cancer are asymptomatic at the time of their relapse and as
such, recurrent ovarian cancer is most frequently detected by elevation of CA125 levels; the
sensitivity and specificity of this test for recurrence detection range from approximately 60–94%
and 91–100%, respectively (168, 169). CA125 levels are monitored following completion of
initial treatment, but guidelines regarding the frequency of CA125 and clinical monitoring of
patients with ovarian cancer changes with differing guidelines (168, 169). The Society of
Gynecologic Oncology recommends a review of clinical symptoms and a physical examination of
patients following initial treatment for ovarian cancer every 3 months with an optional CA125
test and radiographic imaging (CT, PET or MRI) in patients with suspected recurrence (such as
those with an elevated CA125, findings upon clinical examination and/or suspicious symptoms)
29
(169). Conversely, the National Comprehensive Cancer Network guidelines recommend follow-
up visits every 2–4 months for 2 years after treatment, including assessment of CA125 levels and
radiographic imaging if recurrence of ovarian cancer is indicated (142).
The limitations of disease detection and the role of CA125 should be discussed with all patients
who have completed therapy. Sufficient clinical information should be available to make a
definitive diagnosis of cancer recurrence, including elevated CA125 levels, radiographic evidence
of cancer, physical exam evidence, symptoms related to the disease burden and/or a positive
biopsy. Elevated CA125 in the absence of other clinical indicators is generally not a reason to
initiate treatment, unless the patient is enrolling into a clinical trial. Some patients might not have
elevated CA125 levels at either initial diagnosis or with recurrence of ovarian cancer, which
makes the CA125 test less useful when used for recurrent cancer. In these patients, alternative
biomarkers, such as HE4 and/or the use of interval radiographic imaging might be of use for
monitoring of recurrent cancer, but this needs further evaluation. Although used, CA125 for the
early detection of recurrence has not been shown to improve outcomes in patients with recurrent
disease. In one study, no improvement in patient survival was observed following early treatment
of recurrent ovarian cancer (diagnosed on the basis of increased CA125 levels in the absence of
clinical symptoms), compared with delayed treatment (until the manifestation of clinical
symptoms of disease progression) (170). This trial has been criticized because of the long period
of time needed to accrue patients (almost 10 years), the lack of predefined subsequent therapies
and the lack of access to newer treatments (such as bevacizumab) and other drugs through clinical
trials, or to the potential use of secondary cytoreductive surgery (ref).
[H2]Treatment options
Following definitive diagnosis of recurrent ovarian cancer, several factors should be considered
before deciding appropriate treatment options, including the level of disease burden (such as,
symptomatic versus asymptomatic cancer and the location of metastases), the presence of
30
complications from previous therapies (such as peripheral neuropathy, pancytopenias and/or drug
hypersensitivity reactions), availability of clinical trials, degree of platinum sensitivity, end organ
function, performance status of the patient and also, wishes and goals of the patient. Treatment of
recurrent ovarian cancer has been made more complex, with oncologists factoring in tumour
histology and underlying BRCA status, given the recent FDA and EMA approvals of the PARP
inhibitor olaparib.
Secondary surgical cytoreduction can be considered for patients with a long platinum free interval
with recurrent cancer that is limited and isolated, such as cancer in one location such as the spleen
or an isolated lymph node, although meta analyses did not demonstrate any benefit of this surgery
(172). One randomized trial (GOG 213) investigating the efficacy of secondary surgical
cytoreduction for the treatment of platinum-sensitive recurrent ovarian cancer is underway (171).
The German AGO Study Group (Arbeitsgemeisnchaft für Gynäkologische Onkologie) has
demonstrated a potential survival benefit only in patients with no postoperative residual cancer
following secondary cytoreductive surgery (173). This study also established a preoperative
clinical score to predict the target population with the best outcomes following secondary
cytoreductive surgery including the amount of ascites (<500ml) and result of primary surgery
(macroscopically free). On the basis of these findings, a prospective study was conducted
comparing the overall survival of patients with platinum-sensitive recurrent ovarian cancer
undergoing cytoreductive surgery followed by platinum-based chemotherapy, with patients
receiving chemotherapy alone (DESKTOP-Trial III), results of which are expected in 2017 (174).
Recurrent ovarian cancer is classified as platinum-sensitive or platinum-resistant as defined
above. However, the Institute of Medicine called for an improved classification system for
recurrent ovarian cancer, as the current classification does not reflect the effect of BRCA status on
treatment responses and the varied responses to treatment in women with platinum-resistant
31
cancer (179). Additionally, some groups have called for diminishing the importance of the PFI as
this definition is flawed, with no universally accepted objective definition and instead,
incorporating key disease parameters such as molecular signature (such as BRCA mutation),
immunological features and tumor histology (178).
[H3] Platinum-sensitive disease. For patients with platinum-sensitive recurrent ovarian cancer,
the standard of care is re-use of a platinum-based regimen (142). However, re-use of platinum-
based chemotherapy is associated with the development of potentially life threatening platinum
drug allergies (177). Response rates in patients with platinum-sensitive recurrent cancer are
approximately 50% (142, 180-182), although the length of the PFI decreases with subsequent
platinum use (ref). Various combinations of therapies are being investigated for the treatment of
platinum-sensitive ovarian cancer (Table 5), including paclitaxel/carboplatin (180), carboplatin
/pegylated liposomal doxorubicin (181) and carboplatin/gemcitabine (182). Use of a platinum
based combination has been shown to improve outcomes compared with the use of single agent
platinum in patients with a platinum sensitive recurrence (ref)
Approved therapies for the treatment of patients with recurrent, platinum sensitive ovarian cancer
in Europe include bevacizumab (in combination with carboplatin and gemcitabine) and
trabectedin (an agent that binds to DNA, resulting in cell cycle arrest and apoptosis) (182).
Carboplatin and gemcitabine are approved for use in the United States. Trabectedin was not
ultimately approved for use in the United States due to toxicity concerns; adverse effects of this
agent include bone marrow suppression, fatigue and gastrointestinal complications (such as
nausea, vomiting and diarrhoea), in addition to elevation of liver enzymes.
Olaparib has been approved by the EMA as a maintenance therapy for platinum-sensitive ovarian
cancer, after response and completion of platinum-based chemotherapy in patients with either a
32
germline or tumour BRCA mutation. However, accelerated approval for olaparib as a maintenance
therapy in patients with germline BRCA mutations was rejected by the FDA’s Oncologic Drugs
Advisory Committee, due to a lack of evidence supporting improvements in overall survival; the
final results of a confirmatory phase III study (SOLO2) will likely factor into future FDA
decisions (203, 204). Nonetheless, the FDA granted accelerated approval to olaparib as a single
agent for use in patients with germline BRCA mutations who have received at least three prior
lines of chemotherapy, regardless of platinum sensitivity (205).
[H3] Platinum-resistant disease. For patients with platinum-resistant cancer, bevacizumab with
weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan treatment in the first platinum-
resistant setting was approved by both the FDA and EMA, following the results of the AURELIA
trial (187, 188). Although promising, care should be taken when using bevacizumab in patients
with ovarian cancer, due the risk of severe adverse effects, such as gastrointestinal perforation
(189), hypertension, proteinuria and fistula development. Other single agents available to treat
platinum-resistant ovarian cancer include gemcitabine, etoposide and navelbine (142), which
have response rates of up to 10-15% and median PFS of approximately 3-4 months.
Anti-angiogenic agents that have been studied in recurrent ovarian cancer include nintedanib,
trebananib, sunitinib, cabozantinib, and cediranib (190, 191). Notably, cediranib has single agent
activity in both platinum-resistant and platinum-sensitive recurrent ovarian cancer (192), can
increase PFS when combined with platinum-based chemotherapy and can also be used as
maintenance therapy in patients with platinum-sensitive recurrent cancer (185). Also, cediranib is
being tested in combination with olaparib in two actively accruing phase III studies, GY004 and
GY005 (193 and 194).
Ultimately, treatment of recurrent ovarian cancer should be tailored to the patient to prevent
worsening of pre-existing adverse effects such as myelosuppression and neuropathy, as well as
33
respecting the patient’s wishes and the avoidance of other adverse effects such as alopecia and
gastrointestinal complications.
[H1]Quality of life
The diagnosis of any life threatening disease, coupled with the acute and long-term adverse
effects of treatment, can be associated with reductions in quality of life domains, including
physical, functional, emotional, sexual, social and occupational well-being. Moreover, the large
number of medical decisions required in a short period of several days to weeks following initial
diagnosis of ovarian cancer can add to the emotional stress felt by patients. The responses to these
issues varies; for example, some patients might re-evaluate their attitudes to relationships, work
and day-to-day life following a diagnosis of ovarian cancer (220).
Although current treatment advances give more women with ovarian cancer the prospect of living
longer, minimizing and/or ameliorating the adverse effects associated with treatments is crucial if
quality, as well as length, of life is to be improved. Improvements in PFS or overall survival in
trials might excite clinical scientists, but be of less value to patients experiencing treatment-
related adverse effects; because of this, many phase III studies have incorporated standardized,
validated quality of life measures (commonly referred to as patient reported outcome (PRO) end
points) into studies (221, 223). PROs are important as there are increasing doubts raised about the
validity of data regarding adverse events collected during clinical trials; several studies have
shown that the symptoms of disease and adverse effects of treatment are often under-recognized,
under-reported and consequently under-treated (224). Indeed, patients report adverse effects (such
as fatigue, nausea, vomiting, constipation, alopecia, appetite loss and pain) occur earlier, more
frequently and of greater severity than do clinicians and nurses using Common Terminology
34
Criteria for Adverse Events (CTCAE) grading or proxy raters (224).
Quantification of quality of life issues faced by women with ovarian cancer requires well-
constructed, reliable PRO measures that need to be essential components of phase III studies.
Both the FDA and EMA have clear guidelines on PRO instruments that are acceptable for
conducting health technology assessments, defined as outcomes reported by patients, without the
intervention of a third party and that have been constructed using appropriate psychometric
methodology (225). One key issue is that the PRO measures should be defined upfront and during
trial development, with patients involved in their production. PRO measures used for ovarian
cancer include generic, tumor-specific, treatment-specific or symptom-specific measures (226,
228, 229) and involve face-to-face interview schedules (230), quality of life questionnaires (227-
229, 231, 232), satisfaction scales and patient preference approaches (233).
For example, a PRO might include a series of questions related to the severity of various
symptoms, such as lack of energy, pain, discomfort, sexual dysfunction, feeling ill, insomnia,
sweating, bowel control and constipation, as used in the GY004 trial.
Thorough monitoring using validated instruments within clinical trials is needed to compile a
database of the trajectory and severity of issues such as adverse effects of treatment, in addition to
emotional distress, permitting better evaluation of the benefits and harms of therapies, but also to
establish the case for more research to develop therapies to reduce the adverse effects. The
traditional end points of clinical trials (such as PFS and overall survival) need to be integrated
with PROs in order to improve quality as well as quantity of life.
[H1] Outlook
35
Now is a very exciting and promising time for ovarian cancer research, yet challenges remain in
early detection, identification of women who are at higher risk of developing ovarian cancer,
overcoming platinum resistance and resistance to other treatments, in addition to developing
rationale and effective immunotherapeutic strategies.
With the fields of genomics yielding more genetic information about ovarian cancer, in addition
to the genotype of patients and with costs of sequencing dropping, understanding the
pathophysiology and rationale design of therapeutics are poised to move forward. In fact, the
National Comprehensive Cancer Network genetics guidelines as well as several European
organizations have recommended universal germline BRCA mutation screening for all women
diagnosed with ovarian cancer, in order to identify family members at high risk and the risk of the
patient developing other cancers besides ovarian cancer, to allow performance ofrisk reducing
surgeries . Moreover, the extent of genetic testing, including panel testing that includes genes
other than BRCA1 and BRCA2, continues to evolve and will contribute to our understanding of
the genetics underlying formation of ovarian cancer and its biology. Improved understanding of
the genomics of different histological subtypes of ovarian cancer will be an important target over
the upcoming years, to facilitate the understanding of the risk factors associated with this disease,
as well as development of prevention and therapeutic strategies.
Early detection efforts are promising, with ROCA testing demonstrating increased detection of
early ovarian cancers, compared with no testing. However, results of the UKCTOCS study did
not show an overall survival advantage to using the ROCA thus no screening test exists at this
time. Additionally, further research elucidating the role of variant of unknown importance in both
BRCA genes and in other associated genes (such as BRIP1 and RAD51) in the risk of developing
ovarian cancer is critical for the appropriate recommendation of risk-reducing surgeries.
Other risk reducing efforts, including surgical techniques such as bilateral salpingectomy, that are
36
not directed at the high risk population but more at a general risk population are ongoing.
Understanding the pathogenesis of the various types of ovarian cancer, such as the precursor
STIC lesions for HGSC, is critical for the appropriate use of surgical interventions for prevention
of ovarian cancer. Establishing uniform criteria for the definition of the site of origin of HGSC,
based on specific pathology findings, is being called for by consensus statements (93).
[H2] Emerging therapies
Promising future therapies for ovarian cancer include PARP inhibitors and antibody–drug
conjugates. PARP inhibitors, initially olaparib, have shown single agent response rates of up to
30% in recurrent ovarian cancer with the greatest activity in cancers with BRCA mutations and in
platinum-sensitive disease (197-199). Other PARP inhibitors (such as niraparib, rucaparib, and
veliparib) that have single agent activity in ovarian cancer, are in phase III studies of, for
example, use as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer,
following a response to treatment with platinum-based chemotherapy (206, 207) (Table 6);
rucaparib was recently given breakthrough status (to accelerate the development and review of
the drug) by the FDA based on results from the ARIEL2 trial (208). Veliparib has been added to
the NACT armamentarium with carboplatin and paclitaxel for newly diagnosed advanced ovarian
cancer in a phase III study, in addition to testing as a maintenance therapy (209).
Acknowledging that the effectiveness of single agent biologic therapies has reached a therapeutic
plateau, one promising approach has been the development of combinations of biological agents
(anti-angiogenics, PARP inhibitors, and immunotherapy agents) (236, 237, 241, 242). Such a
strategy would target multiple cancer-promoting pathways or mechanisms and might be effective
in particular in HGSC due to its genomic complexity. Other histological subtypes such as clear
cell carcinoma that can harbor deficiencies in homologous recombination, such as mutations
ARID1A and PIK3CA, might also be clinically responsive. Furthermore, biologic combinations
37
have the advantage of including agents that have non-overlapping adverse effects that might
potentially reduce treatment-related toxicities.
Combining PARP inhibitors with targeted therapies against the PI3K pathway is being
investigated, based on pre-clinical evidence from patient-derived xenograft models.
Combinations of PARP inhibitors and, for example, CDK inhibitors, immunotherapy agents and
HSP90 inhibitors (239, 240) are also being assessed. Combining PARP inhibitors with
chemotherapy has already proved challenging due to overlapping myelosuppression associated
with both therapies.
Study of immunotherapy strategies for treatment of recurrent ovarian cancer is underway (213)
with several immune checkpoint inhibitors tested in recurrent disease (Table 6). At this time,
many questions remain about the optimal strategies for the use of immunotherapies for the
treatment of either newly diagnosed or recurrent ovarian cancer, but several studies are planned
and are underway. Combinations of either chemotherapy and immunotherapy or two
immunotherapy agents are under investigation. For example, nivolumab and ipilimumab (which
has shown efficacy in melanoma) compared with nivolumab alone is being investigated, results
from which are pending (235). More research is needed to understand the selection of optimal
immunotherapy through the use of biomarkers, the effect of the tumor microenvironment on
cancer growth and determining best and most effective therapeutic agents and combinations.
Antibody–drug conjugates have shown single agent activity. One antibody drug conjugate,
IMGN853, targets the folate- receptor and is linked to a highly potent maytansinoid that targets
microtubules and suppresses microtubule dynamic instability, inducing cell-cycle arrest and cell
38
death (219). IMGN853 has demonstrated impressive single agent activity in patients with
recurrent platinum-resistant ovarian cancer (219).
One other strategy for therapeutic management of ovarian cancer is replacing mutated TP53 using
gene therapy, as well as inhibition of MDM2 the ligase regulating p53 levels through small
molecules). However, TP53 gene therapy using adenoviral vectors has been met with limited
success partly due to toxicity related to the approaches used (157, 158). Other emerging therapies
targeting tumors carrying mutant TP53 include COTI-2, which is thought to induce a ‘wild-type-
like’ conformational change in mutant p53 and is currently in clinical trials (159).
[H3] Importance of tumour histology. With the improved understanding that ovarian cancer is
composed of several histologically and molecularly distinct subtypes, certain classes of
therapeutics have histology-specific mechanisms of action, such as PARP inhibitors for treatment
of HGSC and MEK inhibitors for treatment of LGSC. Activity of the MEK inhibitor selumetanib
in LGSC has been demonstrated (210); clinical trials comparing the use of MEK inhibitors to
chemotherapy for the treatment of recurrent LGSC are underway; including a phase III study of
binimetinib (also known as MEK162), compared with physician’s choice of chemotherapy agent
(MILO study) (211). However, the MILO study was terminated because of futility, based on a
planned interim analysis showing that the hazard ratio for progression free survival crossed a
predefined futility boundary. One other study assessing MEK inhibition for the management of
LGSC is investigating trametinib (GSK 1120212) in patients with recurrent or progressive LGSC
(212), but this study has been suspended due to problems with the drug supply.
39
[H3] Drug approvals. One challenge for the development of new therapies in ovarian cancer is
the approval mechanisms of the FDA and EMA. Demonstrating an improvement of overall
survival is a requirement for regulatory approval, but is difficult to demonstrate in ovarian cancer;
explanations for this are not fully understood, but possibly include the use of active study agents
after disease progression, which dilutes the effect of the active agent on overall survival but not
on PFS (243, 244). Additionally, the lack of subclassification of histologic subtypes for clinical
trial eligibility might have diluted the efficacy of some therapeutic agents, such as bevacizumab
and also because no biomarker currently exists to select patients to receive this therapy. Several
groups are calling for the achievement of significant improvement in PFS, coupled with PRO
measures demonstrating the benefit of treatment, as a reason for drug approval; approval of
bevacizumab and olaparib was due to improvement in PFS, quality of life, duration of response or
response rate though approvals based on PRO’s are rare (ref). The time frame between
subsequent therapies (that is, the second PFS) or time between paracentesis or thoracentesis
procedures could also be important measurements of patient benefit from a specific therapy.
PROs should be a vital component of any phase III study, particularly those testing agents for
potential regulatory approval for the treatment of ovarian cancer.
Figure 1. Histological subtypes of ovarian cancer.
a | High grade serous carcinoma (HGSC) is characterized by severe nuclear atypia, high nuclear
to cytoplasmic ratio and abundant mitoses. Papillary architecture (arrow) is also often present. b |
Serous tubal intraepithelial carcinoma (STIC) lesions share the same morphological features as
HGSC, with severe atypia, mitoses and lack of polarity. STIC lesions are thought to be precursors
for HGSC. c | Low grade serous carcinoma (LGSC) demonstrates papillary architecture, but only
mild nuclear atypia and a lower nuclear to cytoplasmic ratio. d | Clear cell carcinoma is
characterized by large atypical tumor cells with frequent clearing of the cytoplasm and stromal
hyalinization . e | Endometrioid adenocarcinoma is characterized by gland formation that
recapitulates endometrial glands and is graded based on cellular architecture and nuclear atypia. f
| Mucinous adenocarcinoma shows mucin-filled tumour cells, with frequent goblet cell forms
present.
40
Figure 2. CT scans from a patient with stage IV ovarian cancer
a | Right and left pleural effusions (arrows). b | Peritoneal carcinomatosis (arrows) . c |
Large volume ascites and a peritoneal hepatic implant (arrows)
Figure 3. DNA repair mechanisms and ovarian cancer. A | The double-stranded break and
homologous repair process begins with recognition of the damage by serine-protein kinase ATM
(ATM); a series of steps leads to the recruitment of the BRCA complex. B | DNA mismatch
repair is mediated by the MSH proteins, as well as the endonuclease PMS2 and PCNA. These
DNA repair processes are aberrant in ovarian cancer owing to mutations in the proteins involved.
Figure 4. Tumour burden in ovarian cancer. A | Surgical removal of ovarian tumours in a 63 year old patient with bilateral advanced stage
high grade serous ovarian (HGSC) cancer. B | : Bilateral HGSC with peritoneal carcinomatosis
and involvement of intestinal surfaces C: removal of a serosal tumor implant located on the
surface of the liver
41
Table 1. Characteristics of ovarian cancer by histology, genomic characteristics, and active
therapies
Histological subtype Clinical findings Genetic
characteristics
Treatment options
High grade serous
carcinoma and high-
grade endometrioid
carcinoma
Can present with
peritoneal
carcinomatosis, ascites,
pelvic mass
Typically advanced
stage at presentation
Deficiencies in
homologous
recombination (50% of
tumours) Associated
with BRCA and TP53
mutations
Platinum-based
chemotherapy and
PARP inhibitors
Tumours are initially
sensitive to platinum-
based chemotherapy
but most patients with
advanced-stage cancer
will recur .
Low-grade serous
carcinoma
Presents in younger
patients (median
reported age 43-55
years (95))
Can be early or late
stage at presentation
Associated with KRAS
and BRAF mutations
Tumours havegenomic
stability
MEK inhibitors and
hormonal therapies
Low-grade
endometrioid
carcinoma
Can be associated with
endometriosis
Associated with PTEN,
ARID1A, PIK3CA
mutations. Can have
microsatellite instability
Possible hormonal
therapies (not yet
established)
Clear cell carcinoma Can present with
parenchymal metastases
(in liver and lung)
Can also be associated
with hypercoagulability
and hypercalcaemia.
Associated with
ARID1A and PIK3CA
mutations
Immunotherapy agents.
Can be resistant to
platinum-based
chemotherapy.
Mucinous carcinoma Presents in younger
patients and is typically
early stage at
presentation.
Associated with KRAS
mutations
Tends to be
chemotherapy-
insensitive but are still
treated initially with
cytotoxic
chemotherapy.
MEK, mitogen-activated protein kinase kinase; PARP, poly (ADP ribose) polymerase.
42
Table 2. Functions of commonly mutated inherited genes associated with increased
risk of ovarian cancer18, 22-25
Gene Protein Protein function
BRCA1 Breast cancer type 1
susceptibility protein
Critically involved in the repair of double
strand breaks by homologous recombination
Serves as scaffold for other proteins involved
in double strand DNA repair mostly through
homologous recombination deficiency
BRCA2 stabilizes RAD51-ssDNA complexes
BRCA2 Breast cancer type 2
susceptibility protein
BARD1 BRCA1-associated RING
domain protein 1
Forms a heterodimer with BRCA1
This complex is essential for mutual stability
BRIP1 Fanconi anemia group J
protein
Binds to BRCA1
BRCA1-BRIP1complex is required for S-phase
checkpoint activation
PALB2 Partner and localizer of
BRCA2
Bridging protein that connects BRCA1 and
BRCA2 at sites of DNA damage
Helps load RAD51 onto ssDNA
RAD51C DNA repair protein RAD51
homolog 3
Strand exchange proteins that bind to ssDNA
breaks to form nucleoprotein filaments and
initiate DNA repair RAD51D DNA repair protein RAD51
homolog 4
MSH2
DNA mismatch repair
protein Msh2
Mismatch repair proteins that recognize and
repair basepairing errors occurring during
DNA replication
Mutations in mismatch repair genes are
associated with Lynch syndrome
MLH1 DNA mismatch repair
protein Mlh1
MSH6 DNA mismatch repair
protein Msh6
PMS2 Mismatch repair
endonuclease PMS2
ssDNA, single-stranded DNA.
43
Table 3. Staging of ovarian cancer
FIGO
stage
Description Corresponding
TNM stage
Stage I: Tumor confined to ovaries or fallopian tube(s) T1
IA Tumor limited to one ovary (with ovarian capsule intact) or
fallopian tube; no tumor on ovarian or fallopian tube surface;
no malignant cells in the ascites or peritoneal washings
T1a
IB Tumor limited to both ovaries (with ovarian capsules intact) or
fallopian tubes; no tumor on ovarian or fallopian
tube surface; no malignant cells in the ascites or peritoneal
washings
T1b
IC Tumor limited to one or both ovaries or fallopian tubes, with
any of the following C substages:
T1c
IC1: Surgical spill
IC2: Capsule ruptured before surgery or tumor on ovarian or
fallopian tube surface
IC3: Malignant cells in the ascites or peritoneal washings
Stage II: Tumor involves one or both ovaries, or the fallopian tubes with
pelvic extension below the pelvic brim or primary peritoneal cancer (Tp)
T2
IIA Extension and/or implant of tumour on uterus and/or fallopian
tubes and/or ovaries
T2a
IIB Extension of tumour to other pelvic intraperitoneal tissues T2b
Stage III: Tumor involves one or both ovaries, or the fallopian tubes, or
primary peritoneal cancer with cytologically or histologically confirmed
spread to the peritoneum outside the pelvis and/or metastasis to the
retroperitoneal lymph nodes
T3
IIIA IIIA1: Positive retroperitoneal lymph nodes only
(pathologically proven):
IIIA1(i) Metastasis up to 10 mm in greatest dimension.
IIIA1(ii) Metastasis >10 mm in greatest dimension.
IIIA2: Microscopic extrapelvic (above the pelvic brim)
peritoneal involvement with or without
positive retroperitoneal lymph nodes.
T1, T2, T3aN1
IIIB Macroscopic peritoneal metastasis beyond the pelvis up to 2
cm in greatest dimension, with or without metastasis to the
retroperitoneal lymph nodes
T3b/T3b/N1
IIIC Macroscopic peritoneal metastasis beyond the pelvis > 2 cm in
greatest dimension, with or without metastasis to the
retroperitoneal lymph nodes (includes extension of tumor to
capsule of liver and spleen without parenchymal involvement
of either organ)
T3c/T3cN1
Stage IV: Distant metastasis excluding peritoneal metastases
IVA Pleural effusion with positive cytology. Any T, any N or
M1
IVB Parenchymal metastases and metastases to extra-abdominal
organs (including inguinal lymph nodes and lymph nodes
outside of the abdominal cavity)
Any T, any N or
M1
Adapted from (127). FIGO, The International Federation of Gynecology and Obstetrics;
TNM, TNM Classification of Malignant Tumours.
44
Table 4. Key clinical trials in newly diagnosed ovarian cancer Study Arms
Comments Ref
Adjuvant therapy
GOG 111 IV cisplatin and cyclophosphamide Increase in PFS and overall survival
with cisplatin/paclitaxel treatment.
8
IV cisplatin and paclitaxel
AGO OVAR 3 IV cisplatin and paclitaxel No significant difference between
PFS or overall survival between
treatment arms
10
IV carboplatin and paclitaxel
GOG 158 IV cisplatin and paclitaxel Carboplatin and paclitaxel were not
inferior to cisplatin and paclitaxel
11
IV carboplatin and paclitaxel
GOG 182 IV carboplatin and paclitaxel No significant difference between
PFS or overall survival between
treatment arms
9
Other platinum based doublets
SCOTROC IV carboplatin and paclitaxel Similar PFS between study arms
Less neuropathy observed with
carboplatin and docetaxel treatment
than with carboplatin and paclitaxel
12
IV carboplatin and docetaxel
GOG 172 IV cisplatin and paclitaxel Increase in PFS and overall survival
with IP treatment compared with IV
treatment
143
IP cisplatin and paclitaxel and IV
paclitaxel
JGOG 3016 IV carboplatin and paclitaxel every
21 days
Significant improvement in PFS and
overall survival with dose dense
therapy in patients with sub-optimally
cytoreduced cancer. No difference in
patients with optimally cytoreduced
cancer
144, 145
IV carboplatin every 21 days and
paclitaxel weekly (dose dense
regimen)
GOG 252 IP cisplatin, IV and IP paclitaxel
and bevacizumab
No difference in PFS between study
arms
Higher rates of hypertension, nausea
and vomiting in IP cisplatin group
147
IP carboplatin, IV weekly paclitaxel
and bevacizumab
IV carboplatin, IV weekly
paclitaxel and bevacizumab
MITO-7 Weekly carboplatin and weekly
paclitaxel
No difference in PFS or overall
survival
149
Carboplatin and paclitaxel every 3
weeks
MITO-2 Carboplatin and paclitaxel
No difference in PFS or overall
survival
150
Carboplatin and pegylated
liposomal doxorubicin
Neoadjuvant therapy
45
EORTC Upfront surgery followed by
chemotherapy
NACT followed by surgical
cytoreduction was not inferior to
surgical cytoreduction followed by
adjuvant chemotherapy
160
NACT, interval cytoreductive
surgery, followed by completion of
chemotherapy
Kehoe et al Upfront surgery followed by
chemotherapy
NACT followed by surgical
cytoreduction was not inferior to
surgical cytoreduction followed by
adjuvant chemotherapy
161
NACT, interval cytoreductive
surgery, followed by completion
Maintenance therapy
GOG 218 Carboplatin, paclitaxel and
bevacizumab with bevacizumab
maintenance
Increase in PFS with the addition of
bevacizumab
151
Carboplatin, paclitaxel and
bevacizumab with placebo
maintenance
Carboplatin, paclitaxel and placebo
with placebo maintenance
ICON7 Carboplatin, paclitaxel and
bevacizumab with bevacizumab
maintenance
Increase in PFS with the addition of
bevacizumab
152
Carboplatin and paclitaxel
GOG262 IV carboplatin and paclitaxel every
21 days with or without
bevacizumab
No difference in PFS in intent to treat
patients between dose dense and 21-
day dosing
Increase in PFS in patients receiving
dose-dense treatment versus those
receiving dosing every 21 days who
were not given bevacizumab
No difference in PFS in patients not
receiving bevacizumab
148
IV carboplatin every 21 days and
IV weekly paclitaxel with or
without dose-dense bevacizumab
NCT00866697 Platinum-based chemotherapy and
taxane maintenance therapy
Improved PFS with the addition of
pazopanib
No difference in overall survival
between groups
156
Platinum-based chemotherapy and
taxane maintenance therapy with
pazopanib
AGO-OVAR
12
Carboplatin and paclitaxel
Improved PFS, but more
gastrointestinal toxicities, with
nintedanib.
154
Carboplatin and paclitaxel with
nintedanib
46
NCT01493505 Carboplatin and paclitaxel Results pending 155
Carboplatin and paclitaxel with
trebananib
IP intraperitoneal; IV intravenous; NACT, neoadjuvant chemotherapy; PFS progression-free
survival
47
Table 5. Key trials for treatment of recurrent ovarian cancer.
Study Arms Comments Ref
Platinum-sensitive disease
ICON4/AGO-
OVAR-2.2
Carboplatin
Increase in PFS
and overall
survival with the
addition of
paclitaxel
180
Carboplatin and
paclitaxel
OCEANS Carboplatin, gemcitabine
and bevacizumab with
bevacizumab maintenance
therapy
Increase in PFS
with the addition
of bevacizumab
184
Carboplatin and
gemcitabine
ICON6 Platinum-based
chemotherapy and
cediranib with cediranib
maintenance therapy
Significant
improvement in
PFS
Overall survival
results are
pending
185
Platinum-based
chemotherapy
NOVA Platinum-based
chemotherapy for
platinum-sensitive
recurrence followed by
maintenance niraparib
Significant
improvement in
PFS (in women
with germline
BRCA mutations
or homologous
recombination
deficiency ) group
for niraparib
versus placebo
Ref:
www.Tesarobio.com
press release June
28, 2016 and ESMO
2016 Oct Platinum-based
chemotherapy for
platinum-sensitive
recurrence, followed by
maintenance with placebo
drug
NCT00113607 Pegylated liposomal
doxorubicin and
trabectedin
Pegylated liposomal
doxorubicin
Significant
increase in PFS
with the addition
of trabectedin
186
NCT00753545 Platinum-based
chemotherapy with or
without olaparib
maintenance therapy
Significant
increase in PFS
with olaparib
maintenance
therapy
200
48
NCT01081951 Carboplatin and paclitaxel
with or without olaparib
maintenance therapy
Increase in PFS
with olaparib
maintenance
therapy
201
Platinum-resistant disease AURELIA Paclitaxel with or without
bevacizumab
Increased PFS and
response rate with
the addition of bevacizumab.
Paclitaxel +
bevacizumab was
the best
combination –
increased response
rate, PFS and
overall survival.
187, 188
Pegylated liposomal
doxorubicin with or
withoutbevacizumab
Topotecan with or
withoutbevacizumab
PFS, progression-free survival.
49
Table 6. Ongoing clinical trials for treatment of ovarian cancer
Type of biologic
therapy
Example Target Comments Ref
Anti-angiogenics Bevacizumab
Cediranib
VEGF
VEGFR1, 2, 3
Single agent
activity in both
platinum-resistant
and platinum-
sensitive cancer
184, 185,
187-194
PARP inhibitors Olaparib
PARP Olaparib approved
by the EMA for
treatment of
platinum-sensitive
recurrent cancer as a
maintenance therapy
and by the FDA for
recurrent ovarian
cancer in women
with germline BRCA
mutations and who
have received at
least 3 prior lines of
chemotherapy
193-202,
204-208, 245
Rucaparib Results pending
Veliparib Results pending
Immunotherapies Nivolumab
Programmed
cell death
protein-1
15% response rate
and 50% disease
control rate
214
Pembrolizumab
Programmed
cell death
protein-1
11.5% response rate
and 23.1% of
patients had stable
disease
215
50
Avelumab Programmed
cell death 1
ligand 1
10.7% risk reduction
and 54.7% disease
control rate. 2
patients with a clear
cell histology
showed evidence of
an objective
response rate.
216
Ipilimumab Cytotoxic T-
lymphocyte
protein 4
Results pending 217, 218
Antibody–drug
conjugate
IMGN853 Folate receptor
Promising
preliminary data
219
Combination Cediranib and
olaparib
Various Increased PFS in
patients that
received
cediranib/olaparib,
compared with
patients receiving
olaparib alone.
Currently being
tested in phase III
studies in both
platinum-resistant as
well as platinum-
sensitive recurrent
cancer
193, 194, 238
Pembrolizumab
and niraparib
Results pending 240
BKM120 or
BYL719 and
olaparib
Maximum tolerated
dose achieved for
BKM120 and
olaparib; anti-cancer
activity noted for
this combination
239
References
1) Callegaro-Filho D et al. Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): A review of
47 cases, Gyn Onc 140, 53-57 (2016).
2) del Carmen, MG et al .Carcinosarcoma of the ovary: A review of the literature Gyn Onc 125, 271-
277(2012).
51
3) Kindelberger DW et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence
for a causal relationship. Am J Surg Pathol 31,161–9 (2007).
4) Kurman RJ et al. WHO Classification of Tumours of Female Reproductive Organs. Fourth Edition.
Lyon, France: IARC; 2014.
5) Goff BA, et al. Ovarian carcinoma diagnosis. Cancer 89, 2068-75 (2000).
6) Menon U, et al. Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-
Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of
Ovarian Cancer Screening. J Clin Oncol. 33, 2062-71 (2015).
7) Jacobs IJ, Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS): a randomised controlled trial. Lancet. S0140-6736(15)01224-6. (2016).
8) McGuire WP, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients
with stage III and stage IV ovarian cancer. N Engl J Med.334, 1-6 (1996).
9) Bookman MA et al Evaluation of new platinum-based treatment regimens in advanced-stage ovarian
cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009 20, 1419-25 (2009).
10) du Bois A, et al. Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group. A
randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of
ovarian cancer. J Natl Cancer Inst. 95, 1320-1329 (2003).
11) Ozols RF, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in
patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin
Oncol. 21, 3194-3200 (2003).
12) Vasey PA, et al. Scottish Gynaecological Cancer Trials Group. Phase III randomized trial of docetaxel-
carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer
Inst. 17, 1682-91 (2004).
13) Siegel RL, Miller KD, Jemal A. Cancer Statistics 2016. CA Cancer J Clin. 66,7-30 (2016)
14) Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global Cancer Statistics. CA Cancer J Clin.
61, 69-90 (2011).
15) Sant M, et al. Survival of women with cancers of breast and genital organs in Europe 1999-2007:
results of the EUROCARE-5 study Eur J Cancer. 2015 Sep 6. pii: S0959-8049(15)00702-9
16) http://seer.cancer.gov/statfacts/html/ovary.html
17) Castilla LH, et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.
Nat Genet. 8, 387–391 (1994).
18) Pennington KP, Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol.
124, 347-53 (2012)
19) Bolton KL, et al. Association between BRCA1 and BRCA2 mutations and survival in women with
invasive epithelial ovarian cancer. JAMA. 307, 382-90 (2012).
52
20) Liu G, et al. Differing clinical impact of BRCA1 and BRCA2 mutations in serous ovarian cancer.
Pharmacogenomics 13, 1523-35 (2012).
21) Rebbeck TR, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of
breast and ovarian cancer. JAMA. 313, 347-61 (2015).
22) Walsh T, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma
identified by massively parallel sequencing. Proc Natl Acad Sci U S A.108, 18032-7 (2011)
23) Norquist, BM, et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncology Dec
30:1-9. doi: 10.1001/jamaoncol.2015.5495 (2015).
24) Prakash R, Zhang Y, Feng W and Jasin M. Homologous recombination and Human Health: The roles
of BRCA1, BRCA2 and associated proteins. Cold Spring Harbor Perspectives in Biology,7:1-27 (2015)
25) Suwaki N, Klare K, and Tarsounas M. RAD51 paralogs; Roles in DNA damage signaling,
recombinational repair, and tumorigenesis. Seminars In Cell Devel Biol 22,898-905 (2011).
26) Ketabi Z, Bartuma K, Bernstein I, et al. Ovarian cancer linked to Lynch syndrome typically presents as
early-onset, non-serous epithelial tumors. Gynecol Oncol 121,462–465 (2011).
27) Engel C, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin
Oncol. 30,4409–4415 (2012).
28) Crispens MA. Endometrial and ovarian cancer in lynch syndrome. Clin Colon Rectal Surg. 25,97–102
(2012).
29) Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation
carriers: systematic review and meta-analysis. J Natl Cancer Inst. 106, (2014).
30) Moorman PG, et al. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk
women: a systematic review and meta-analysis. J Clin Oncol. 31, 4188-98 (2013).
31) Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable
risks of cardiovascular disease, cancer, and other health outcomes Ann Epidemiol. 25,193-200 (2015).
32) Havrilesky LJ,et al. Oral contraceptive use for the primary prevention of ovarian cancer. Evid Rep
Technol Assess (Full Rep). 212,1-514 (2013).
33) Pearce CL, et al: Increased ovarian cancer risk associated with menopausal estrogen therapy is reduced
by adding a progestin. Cancer 115, 531-539 (2009).
34) Mørch LS, et al: Hormone therapy and ovarian cancer. JAMA 302,298-305 (2009).
35) Hildebrand JS, et al: Postmenopausal hormone use and incident ovarian cancer: Associations differ by
regimen. Int J Cancer 127,2928-2935 (2010).
36) Collaborative Group On Epidemiological Studies Of Ovarian Cancer, Beral V, Gaitskell K, Hermon C,
Moser K, Reeves G, Peto R. Menopausal hormone use and ovarian cancer risk: individual participant meta-
analysis of 52 epidemiological studies. Lancet. 385, 835-42 (2015).
37) Yang HP, Anderson WF, Rosenberg PS, Trabert B, Gierach GL, Wentzensen N, Cronin KA, Sherman
ME Ovarian cancer incidence trends in relation to changing patterns of menopausal hormone therapy use in
the United States. J Clin Oncol. 2013 Jun 10;31(17):2146-51
38) Eeles RA et al. Adjuvant Hormone Therapy May Improve Survival in Epithelial Ovarian Cancer:
53
Results of the AHT Randomized Trial. J Clin Oncology J of Clin Oncol 10, 4138-44 (2012)
39) Falconer H, Yin L, Grönberg H, Altman D. Ovarian cancer risk after salpingectomy: a nationwide
population-based study. J Natl Cancer Inst. 107, (2015).
40) McAlpine JN, et al. Ovarian Cancer Research Program of British Columbia. Opportunistic
salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. Am J
Obstet Gynecol. 210, e1-11 (2014).
41) Kwon JS,et al. Costs and benefits of opportunistic salpingectomy as an ovarian cancer prevention
strategy. Obstet Gynecol. 125, 338-45 (2015).
42) Rice MS, Hankinson SE, Tworoger SS. Tubal ligation, hysterectomy, unilateral oophorectomy, and risk
of ovarian cancer in the Nurses' Health Studies. Fertil Steril. 102,192-198 (2014).
43) Gaitskell K, Green J, Pirie K, Reeves G; Valerie Beral; on behalf of the Million Women Study
Collaborators. Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by histological
type. Int J Cancer. Sep 17 (2015).
44) Kotsopoulos J, et al. Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin Int J
Cancer. 133, 730-9 (2013).
45) NaNa Keum, DC, et al.Adult Weight Gain and Adiposity-Related Cancers: A Dose-Response Meta-
Analysis of Prospective Observational Studies J of the National Cancer Institute 107(2015).
46) Cannioto RA and Moysich KB. Epithelial ovarian cancer and recreational physical activity: A review
of the epidemiological literature and implications for exercise prescription. Gyn Onc 137,559-573 (2015).
47) Nagle CM, et al. Obesity and survival among women with ovarian cancer: results from the Ovarian
Cancer Association ConsortiumBBr J Cancer. 113,817-26 (2015).
48) Huang T, et al. Depression and risk of epithelial ovarian cancer: Results from two large prospective
cohort studies. Gynecol Oncol. S0090-8258, 30153-0 (2015).
49) Merritt MA, Poole EM, Hankinson SE, Willett WC, Tworoger SS. Dairy food and nutrient intake in
different life periods in relation to risk of ovarian cancer. Cancer Causes Control. 25, 795-808 (2014).
50) Terry KL et al. Genital powder use and risk of ovarian cancer: a pooled analysis of 8525 cases and
9859 controls. Cancer Prev Research 6, 811-821 (2013)
51) Houghton SC, et al. Perineal powder use and risk of ovarian cancer. J Natl Cancer Inst. 106(9) (2014).
52) Narod S. Talc and ovarian cancer. Gyn Oncol http://dx.doi.org/10.1016/j.ygyno.2016.04.011 (2016)
53) Koushik A, et al.. Intake of vitamins A, C, and E and folate and the risk of ovarian cancer in a pooled
analysis of 10 cohort studies. Cancer Causes Control. 26, 1315-27 (2015).
54) Xie J, et al. A prospective cohort study of dietary indices and incidence of epithelial ovarian cancer. J
Ovarian Res. 7:112 (2014).
55) Cassidy A, Huang T, Rice MS, Rimm EB, Tworoger SS. Intake of dietary flavonoids and risk of
epithelial ovarian cancer. Am J Clin Nutr. 100, 1344-51 (2014).
56) Trabert B, et al.; Ovarian Cancer Association Consortium. Aspirin, nonaspirin nonsteroidal anti-
inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis
in the Ovarian Cancer Association Consortium. J Natl Cancer Inst. 106, (2014).
54
57) Walker JL, et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian
cancer. Cancer. doi: 10.1002/cncr.29321 (2015).
58) National Comprehensive Cancer Network: genetics guidelines. Available from http://www.nccn.org.
59) Kurman RJ, Shih IM. The origin and pathogenesis of epithelial ovarian cancer; a proposed unifying
theory. Am J Surg Pathol. 34:433-443 (2010).
60) Medeiros F, Muto MG, Lee Y. et al The tubal fimbria is a preferred site for early adenocarcinoma in
women with familial ovarian cancer syndrome. Am J Surg Pathol 30, 230-236 (2006).
61) Carlson JW, Miron A, Jarboe EA, et al. Serous tubal intraepithelial carcinoma; its potential role in
primary peritoneal serous carcinoma and serous cancer prevention. J Clin Oncol 26, 4160-4165 (2008).
62) Finch APM et al. Impact of Oophorectomy on Cancer Incidence and mortality in women with a
BRCA1 or BRCA2 mutation. JCO 32:1547-1553 (2014).
63) Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-15
(2011).
64) Konstantinopoulos P et al, Cancer Discovery 5, 1137-54, 2015.
65) Berns EM, Bowtell DD. The changing view of high-grade serous ovarian cancer. Cancer Res 72, 2701-
4 (2012)
66) Patch AM, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 521, 489-94
(2015).
67) Liu J, Matulonis UA. New strategies in ovarian cancer: translating the molecular complexity of ovarian
cancer into treatment advances. Clin Cancer Res.20, 5150-6 (2014).
68) Galic V, Coleman RL, Herzog TJ. Unmet needs in ovarian cancer: dividing histologic subtypes to
exploit novel targets and pathways. Curr Cancer Drug Targets 13:698-707, (2013).
69) Ahmed AA,et al. .Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary.
J Pathol. 221, 49-56 (2010).
70) Zhang S, Royer R, Li S, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected
patients with invasive ovarian cancer. Gynecol Oncol. 121,353-357 (2011).
71) Alsop K, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-
positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin
Oncol 30,2654-63 (2012).
72) O’Donovan PJ, Livingston DM. BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene
products and participants in DNA double-strand break repair. Carcinogenesis. 2010;31(6):961-967.
73) Hennessy BT,et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that
benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol. 28, 3570-6 (2010).
74) Pennington KP, et al. Germline and somatic mutations in homologous recombination genes predict
platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res
20,764-75 (2014).
75) Eccles DM, Mitchell G, Monteiro AN, Schmutzler R, Couch FJ, et al. BRCA1 and BRCA2
55
genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol. 26, 2057-65 (2015).
76) Bashashati A, Ha G, Tone A, Ding J, Prentice LM, Roth A, et al. Distinct evolutionary trajectories of
primary high-grade serous ovarian cancers revealed through spatial mutational profiling. J Pathol. 231, 21-
34 (2013).
77) Baratta MG, et al. An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a
potential therapeutic target in ovarian carcinoma. Proc Natl Acad Sci U S A. 112, 232-7 (2015).
78) Reyes-González JM, et al. Targeting c-MYC in Platinum-Resistant Ovarian Cancer Mol Cancer Ther.
2015 Jul 30
79) Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous
and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008;14:5198-208.
80) Bentink S, Haibe-Kains B, Risch T, Fan JB, Hirsch MS, Holton K, et al. Angiogenic mRNA and
microRNA gene expression signature predicts a novel subtype of serous ovarian cancer. PLoS One
2012;7:e30269.
81) Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, et al. Prognostically relevant
gene signatures of high-grade serous ovarian carcinoma. J Clin Invest 2013;123:517-25.
82) Yang D, Sun Y, Hu L, Zheng H, Ji P, Pecot CV, Zhao Y, Reynolds S, Cheng H, Rupaimoole R,
Cogdell D, Nykter M, Broaddus R, Rodriguez-Aguayo C, Lopez-Berestein G, Liu J, Shmulevich I, Sood
AK, Chen K, Zhang W. Integrated analyses identify a master microRNA regulatory network for the
mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013 Feb 11;23(2):186-99.
83) Etemadmoghadam D, deFazio A, Beroukhim R, et al. Integrated genome-wide DNA copy number and
expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Clin
Cancer Res. 15:1417-1427 (2009).
84) Berchuck A, Iversen ES, Lancaster JM, Pittman J, Luo J, Lee P, Murphy S, Dressman HK, Febbo PG,
West M, Nevins JR, Marks JR. Patterns of gene expression that characterize long-term survival in
advanced stage serous ovarian cancer Clin Cancer Res. 11:3686-96 (2005).
85) Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, Levine DA,
Cannistra SA. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy
and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010 Aug 1;28(22):3555-61. doi:
10.1200/JCO.2009.27.5719. Epub 2010 Jun 14. Erratum in: J Clin Oncol. 28:4868 (2010).
86) Crum CP, Herfs M, Ning G, et al.. Through the glass darkly: intraepithelial neoplasia, top-down
differentiation, and the road to ovarian cancer. J Pathol. 231, 402–412 (2013).
87) Perets R, et al.. Transformation of the fallopian tube secretory epithelium leads to high-grade serous
ovarian cancer in Brca;Tp53;Pten models. Cancer Cell. 24,751–765 (2013).
88) Lee Y, , et al.. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J
Pathol. 211:26–35 (2007).
89) Powell CB, et al.. Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected
neoplasia identified at risk reducing salpingo-oophorectomy. Gynecol Oncol. 129,364–371 (2013).
90) Conner JR, et al.. Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-
56
oophorectomy in women with germ-line BRCA1 or BRCA2 mutations. Gynecol Oncol. 132, 280–286
(2014).
91) Howitt BE, et al. Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation
status, histology, and tubal intraepithelial carcinoma Am J Surg Pathol. 39, 287-93 (2015).
92) Soslow RA, et al.. Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian
carcinoma. Mod Pathol. 25,625–636 (2012).
93) Singh N et al. Primary site assignment in tubo-ovarian high grade serous carcinoma: Consensus
statement on unifying practice worldwide. Gynecol Oncol 141, 195-198 (2016).
94) Tan DS, et al. Genomic analysis reveals the molecular heterogeneity of ovarian clear cell carcinomas.
Clin Cancer Res 17, 1521-34 (2011).
95) Della Pepa C, et al. Low Grade Serous Ovarian Carcinoma: from the molecular characterization to the
best therapeutic strategy. Cancer Treat Rev. 41, 136-43 (2015).
96) Romero I, Sun CC, Wong KK, Bast RC Jr, Gershenson DM. Low-grade serous carcinoma: new
concepts and emerging therapies. Gynecol Oncol. 130, 660-6 (2013).
97) Tone AA, et al. Intratumoral heterogeneity in a minority of ovarian low-grade serous carcinomas BMC
Cancer. 14, 982 (2014).
98) Oswald AJ and Gourley C. Low grade epithelial ovarian cancer: a number of distinct clinical entities?
Curr Opin Oncol 27, 412-419 (2015).
99) Wiegand KC, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. New Engl J
Med 363:1532-43, (2010).
100) Groen RS, Gershenson DM, Fader AN. Updates and emerging therapies for rare epithelial ovarian
cancers: one size no longer fits all. Gynecol Oncol 136,373-383 (2015).
101) Mangili G, et al. Unraveling the two entities of endometrioid ovarian cancer: a single center clinical
experience. Gynecol Oncol 126, 403-407 (2012).
102) Brown J, Frumovitz M. Mucinous tumors of the ovary: current thoughts on diagnosis and
management. Curr Oncol Rep 2014;16:389. In press.
103) Ryland GL,et al. Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors
Genome Med. 7;7(1):87 (2015).
104) Jelinic P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet. 46,
424-6 (2014).
105) Ramos P, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating
germline and somatic mutations in SMARCA4. Nat Genet. 46, 427-9 (2014).
106) Zhang L, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J.
Med. 348, 203–213 (2003).
107) Hwang WT, et al. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-
analysis. Gynecol Oncol 124, 192–198 (2012).
108) Musrap N, Diamandis EP. Revisiting the complexity of the ovarian cancer microenvironment--clinical
implications for treatment strategies. Mol Cancer Res 10,1254-64 (2012).
57
109) Zsiros E, Tanyi J, Balint K, Kandalaft LE. Immunotherapy for ovarian cancer: recent advances and
perspectives. Curr. Opin. Oncol. 26, 492–500 (2014).
110) Schlienger K, et al. TRANCE- and CD40 ligand-matured dendritic cells reveal MHC class I-restricted
T cells specific for autologous tumor in late-stage ovarian cancer patients. Clin Cancer Res 9, 1517–1527
(2003).
111) Santin AD, et al. In vitro induction of tumor-specific human lymphocyte antigen class I-restricted
CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients
with advanced ovarian cancer. Am J Obstet Gynecol 183:601–609 (2000).
112) Yang X, Shen F, Hu W, Coleman RL, Sood AK New ways to successfully target tumor vasculature in
ovarian cancer. Current Opinion in Obstetrics and Gynecology 27, 58-65 (2015).
113) Bottsford-Miller JN, Coleman RL, Sood AK Resistance and escape from anti-angiogenesis therapy:
Clinical implications and future strategies. Journal of Clinical Oncology 30, 4026-4034 (2012).
114) Lu C, et al Gene alterations identified by expression profiling in tumor-associated endothelial cells
from invasive ovarian carcinoma. Cancer Research 67, 757-768 (2007).
115) Goff BA, et al.: Frequency of symptoms of ovarian cancer in women presenting to primary care
clinics. JAMA 291, 2705-12, (2004)
116) Demir RH, Marchand GJ. Adnexal masses suspected to be benign treated with laparoscopy. Journal of
the Society of Laparoendoscopic Surgeons 16,71-84 (2012).
117) Kobayashi H, et al.: A randomized study of screening for ovarian cancer: a multicenter study in Japan.
Int J Gynecol Cancer 18, 414-20 (2008).
118) Jacobs IJ, et al.: Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 353,1207-10
(1999).
119) Miller JW et al. Physicians' beliefs about effectiveness of cancer screening tests: A national survey of
family physicians, general internists, and obstetrician–gynecologists
Prev Med. 69, 37-42 (2014).
120) Buys SS, et al.: Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and
Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 305, 2295-303 (2011).
121) Menon U, et al.: Sensitivity and specificity of multimodal and ultrasound screening for ovarian
cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative
Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 10,327-40 (2009)
122) Pinsky PF, et al.: Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality
outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial. Int J Cancer 132, 2127-33 (2013).
123) Skates SJ, et al. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical
detection in postmenopausal women. J Clin Oncol 206s–10s (2003).
124) Hellstrom I, et al. The HE4 (WFDC2) Protein is a biomarker for ovarian carcinoma. Cancer Research
63,3695-3700 (2003).
125) Wu L, Dai ZY, Qian YH, Shi Y, Liu FJ, Yang C. Diagnostic value of serum human epididymis
protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. International Journal of
Gynecological Cancer 22, 1106-1112 (2012).
58
126) Maritschnegg E, et al. Lavage of the Uterine Cavity for Molecular Detection of Müllerian Duct
Carcinomas: A Proof-of-Concept Study. J Clin Oncol. 33, 4293-300 (2015).
127) Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary,
fallopian tube, and peritoneum. Int J Gynecol Obstet. 124:1-5 (2014).
128) Ferrandina G, Scambia G, Legge F, Petrillo M, Salutari V. Ovarian cancer patients with “node
positive-only” Stage IIIC disease have a more favorable outcome than Stage IIIA/B. Gynecol Oncol 107,
154–6 (2007).
129) Baek SJ, et al. Stage IIIC epithelial ovarian cancer classified soley by lymph node metastasis has a
more favorable prognosis than other types of stage IIIC epithelial ovarian cancer. J Gynecol Oncol 19,
223–8 (2008).
130) Mayer AR, et al. Ovarian cancer staging: does it require a gynecologic oncologist? Gynecol Oncol
47:223-7, (1992).
131) Chan JK, et al. Influence of the gynecologic oncologist on the survival of ovarian cancer patients.
Obstet Gynecol 109, 1342-50 (2007).
132) Cliby WA, et al. Ovarian cancer in the United States: contemporary patterns of care associated with
improved survival. Gynecol Oncol. 136, 11-7 (2015).
133) Bristow RE, Chang J, Ziogas A, Anton-Culver H. Adherence to treatment guidelines for ovarian
cancer as a measure of quality care. Obstet Gynecol 121,1226-34 (2013).
134) Chang SJ, Bristow RE, Ryu HS. Impact of complete cytoreduction leaving no gross residual disease
associated with radical cytoreductive surgical procedures on survival in advanced ovarian cancer. Ann Surg
Oncol 19,4059-67 (2012).
135) Chang SJ, Hodeib M, Chang J, Bristow RE. Survival impact of complete cytoreduction to no gross
residual disease for advanced-stage ovarian cancer: a meta-analysis Gynecol Oncol. 130, 493-8 (2013).
136) Horowitz NS, et al. Does aggressive surgery improve outcomes? Interaction between preoperative
disease burden and complex surgery in patients with advanced-stage ovarian cancer: an analysis of GOG
182. J Clin Oncol. 33, 937-43 (2015).
137) Bagley CM, Jr., Young RC, Schein PS, Chabner BA, DeVita VT. Ovarian carcinoma metastatic to the
diaphragm--frequently undiagnosed at laparotomy. A preliminary report. Am J Obstet Gynecol 116, 397-
400 (1973).
138) Piver SM, Barlow J, Lele SB. Incidence of subclinical metastasis in stage I and II ovarian carcinoma.
Obstet Gynecol 52, 100-4 (1978).
139) Piver SM. Optimal surgical therapy in stage I and II ovarian malignancies. Int J Radiat Oncol Biol
Phys 1982;8.
140) Mayer AR, et al. Ovarian cancer staging: does it require a gynecologic oncologist? Gynecol Oncol 47,
223-7 (1992).
141) McGowan L, Lesher LP, Norris HJ, Barnett M. Misstaging of ovarian cancer. Obstet Gynecol 65,
568-72 (1985).
59
142) National Comprehensive Cancer Center Ovarian cancer treatment guidelines, accessed on November
6, 2015: www.nccn.org
143) Armstrong DK, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354, 34-
43 (2006).
144) Katsumata N, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks
for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. The Lancet 374, 1331-8
(2009).
145) Katsumata N,et al. Japanese Gynecologic Oncology Group. Long-term results of dose-dense
paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced
epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled,
open-label trial. Lancet Oncol. 14, 1020-6 (2013).
146) Wright AA, et al. Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian
Cancer. J Clin Oncol. 33, 2841-7 (2015).
147) Walker J et al. A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian,
fallopian tube and primary peritoneal carcinoma: GOG 252. Abstract presented at Society of Gynecologic
Oncology annual meeting, 2016.
148) Chan J, et al. Phase III trial of every-3-weeks paclitaxel versus dose dense weekly paclitaxel with
carboplatin +/- bevacizumab in epithelial ovarian, peritoneal, fallopian tube cancer: GOG 262 N Engl J
Med.374,738-48 (2016).
149) Pignata S, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with
advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 15,
396-405 (2014).
150) Pignata S, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin
as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. Journal of
Clinical Oncology 29, 3628-35 (2011).
151) Burger RA, et al. for the Gynecologic Oncology Group. Incorporation of bevacizumab in the primary
treatment of ovarian cancer. The New England Journal of Medicine 365, 2473-83 (2011).
152) Perren TJ,et al. A phase 3 trial of bevacizumab in ovarian cancer. New England Journal of Medicine
365, 2484-96 (2011).
153) Oza AM, et al. Standard chemotherapy with or without bevacizumab for women with newly
diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 16,
928-36 (2015).
154) du Bois A, et al. Standard first-line chemotherapy with or without nintedanib for advanced cancer
(AGO-OVAR 12): A randomized, placebo-controlled phase 3 trial Lancet Oncol. 17:78-89 (2016)...
155) US National Library of Medicine. ClinicalTrials.gov [online],
http://clinicaltrials.gov/ct2/show/NCT01493505 (2011))
156) du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M, et al. Incorporation of
pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol. 32, 3374-82 (2014).
157) Vazquez, A. et al. The genetics of the p53 pathway, apoptosis and cancer therapy. Nature Rev. Drug
Discov. 7, 979–987 (2008)
60
158) Cheok, C. F. et al. Translating p53 into the clinic. Nature Rev. Clin. Oncol. 8, 25–37 (2011)
159) Liu Y, et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature. 520, 697-701
(2015).
160) Vergote I, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.N
Engl J Med. 363, 943-53 (2010).
161) Kehoe S, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian
cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 386, 249-57
(2015).
162) Gómez-Hidalgo NR, Martinez-Cannon BA, Nick AM, Lu KH, Sood AK, Coleman RL, Ramirez
PT.Predictors of optimal cytoreduction in patients with newly diagnosed advanced-stage epithelial ovarian
cancer: Time to incorporate laparoscopic assessment into the standard of care. Gynecol Oncol. 137, 553-8
(2015).
163) du Bois A, Marth C, Pfisterer J, Harter P, Hilpert F, Zeimet AG, Sehouli J.
Neoadjuvant chemotherapy cannot be regarded as adequate routine therapy strategy of advanced ovarian
cancer. Int J Gynecol Cancer. 22,182-5 (2012).
164) Mahner S. et al. Neoadjuvant chemotherapy in ovarian cancer revisited. Ann Oncology 2016,
supplement 1li30-i32. 160) Markman M. Maintenance chemotherapy in the management of epithelial
ovarian cancer. Cancer Metastasis Rev 34:11-17, (2015).
165) Markman M. Maintenance chemotherapy in the management of epithelial ovarian cancer. Cancer
Metastasis Rev 34:11-17 (2015)
166) Mei et al. Maintenance chemotherapy for ovarian cancer. Cochrane Database System Rev. Jun
29;6:CD007414 (2013).
167) Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD, Jiang C, Alberts D;
Southwest Oncology Group; Gynecologic Oncology Group. Phase III randomized trial of 12 versus 3
months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to
platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology
Group trial. J Clin Oncol. 21, 2460-5 (2003).
168) Rustin GJ, Marples M, Nelstrop AE, Mahmoudi M, Meyer T. Use of CA-125 to define progression of
ovarian cancer in patients with persistently elevated levels. J Clin Oncol 19, 4054–57 (2001).
169) Salani R, Backes FJ, Fung MF, Holschneider CH, Parker LP, Bristow RE, Goff BA. Posttreatment
surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic
Oncologists recommendations. Am J Obstet Gynecol. 204, 466-78 (2011).
170) Rustin GJ, van der Burg ME, Griffin CL, Guthrie D, Lamont A, Jayson GC, Kristensen G, Mediola C,
Coens C, Qian W, Parmar MK, Swart AM; MRC OV05; EORTC 55955 investigators. Early versus delayed
treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 376, 1155-
63 (2010).
171) GOG 213) (US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00565851 (2007)).
172) Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, Galaal K. Surgical
cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev. 2:CD008765. (2013).
61
173) Harter P,et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische
Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol. 13, 1702-10 (2006).
174) DESKTOP 3(US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT01166737 (2010)).
175) Markman M, et al. Second-line platinum therapy in patients with ovarian cancer previously treated
with cisplatin. J Clin Oncol. 9, 389-93 (1991).
176) Blackledge G, et al. Response of patients in phase II studies of chemotherapy in ovarian cancer:
implications for patient treatment and the design of phase II trials. Br J Cancer 59, 650-653 (1989).
177) Castells MC, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid
desensitization in 413 cases. J Allergy Clin Immunol. 122, 574-80 (2008).
178) Alvarez R, Matulonis U, Coleman R, Herzog T, Monk B, and Markman M. Moving Beyond the
Platinum Sensitive/Resistant Paradigm for Patients with Recurrent Ovarian Cancer, in press Gynecol
Oncology 2016.
179) http://www.nationalacademies.org/hmd/Reports/2016/state-of-ovarian-cancer.aspx
180) Parmar MK, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based
chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 361,
2099-106 (2003).
181) Pujade-Lauraine E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel
and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. Journal of Clinical
Oncology 28, 3323-9 (2010).
182) Pfisterer J, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-
sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC
GCG. J Clin Oncol. 24, 4699-707 (2006).
183) Raja FA, et al. Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent
ovarian cancer: a meta-analysis using individual patient data. Ann Oncol.24, 3028-34 (2013).
184) Aghajanian C, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of
chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian,
primary peritoneal, or fallopian tube cancer. J Clin Oncol. 30, 2039-45 (2012).
185) Ledermann J, et al. Cediranib in patients with relapsed platinum sensitive ovarian cancer (ICON6); a
randomised double-blind phase III trial Lancet 387, 1066-74 (2016).
186) Monk BJ et al. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer JCO 28:3107-
3114 (2010)
187) Pujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent
ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 32, 1302-8 (2014).
188) Poveda AM, et al. Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal
Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy
Cohort of the Randomized Phase III AURELIA Trial. J Clin Oncol.63, 1408 (2015).
189) Cannistra SA,et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer
or peritoneal serous cancer. J Clin Oncol. 25, 5180-6 (2007).
62
190) Gadducci A, Lanfredini N, Sergiampietri C. Antiangiogenic agents in gynecological cancer: State of
art and perspectives of clinical research. Crit Rev Oncol Hematol. 96,113-28 (2015).
191) Jackson AL, Eisenhauer EL, Herzog TJ. Emerging therapies: angiogenesis inhibitors for ovarian
cancer. Expert Opin Emerg Drugs. 20, 331-46 (2015).
192) Matulonis UA, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor
kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol.
27, 5601-6 (2009)..
193) US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT02446600 (2016). GY004
194) US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT02502266 (2016).GY005
195) Liu JF, Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: current status and
future promise. Gynecol Oncol 133, 362-9 (2014).
196) Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and
future development. J Clin Oncol. 33, 1397-406 (2015).
197) Audeh MW, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or
BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245-51 (2010).
198) Gelmon KA, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian
carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet
Oncology. 12852-61 (2011).
199) Matulonis UA et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a
germline BRCA1/2 mutation: a multi-study analysis of response rates and safety.Ann Oncol. 2016 Mar 8.
pii: mdw133. [Epub ahead of print]
200) Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J
Med 366,1382-92 (2012).
201) Oza AM, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer:
a randomised phase 2 trial. Lancet Oncol. 16, 87-97 (2015).
202) Ledermann J, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous
ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
Lancet Oncology 15, 852-61 (2014).
203) http://www.fda.gov/AdvisoryCommittees/Calendar/ucm394126.htm
204) US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01874353 (2013).
205) Kaufman B, et al Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2
mutation. J Clin Oncol. 33, 244-50 (2015).
206) Sandhu SK, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation
carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncology 14, 882-892
(2013).
63
207) Coleman RL, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in
the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in
patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology
Group study. Gynecol Oncol. 137, 386-91 (2015).
208) McNeish, IA, et al. Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer
patients likely to respond to rucaparib using tumor genetic analysis. Clin Oncol 33, 2015 (suppl; abstr
5508).
209) (US National Library of Medicine. ClinicalTrials.gov [online],
http://clinicaltrials.gov/ct2/show/NCT02470585 (2015))
210) Farley J, et al. Selumetanib in women with recurrent low-grade serous carcinoma of the ovary or
peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 14, 134-40 (2013).
211) (US National Library of Medicine. ClinicalTrials.gov [online],
http://clinicaltrials.gov/ct2/show/NCT01849874 (2013))
212) (US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT02101788 (2014)).
213) Coukos G et al. Opportunities in Immunotherapy of Ovarian cancer. Ann Oncol. 2016 Apr;27 Suppl
1:i11-i15
214) Hamanishi J, et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients
With Platinum-Resistant Ovarian Cancer. J Clin Oncol. 62.3397 (2015).
215) Varga A, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive
advanced ovarian cancer: Interim results from a phase Ib study. J Clin Oncol 33, 2015 (suppl; abstr 5510)
216) Disis ML, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously
treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial. J Clin Oncol 33,
2015 (suppl; abstr 5509)
217) Hodi FS, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-
associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 105, 3005-10
(2008).
218) (US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT01611558 (2014)).
219) Moore, KN, et al. Preliminary single agent activity of IMGN853, a folate receptor alpha (FRα)-
targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients
(pts): Phase I trial. J Clin Oncol 33, 2015 (suppl; abstr 5518).
220) Park, Crystal L.; Edmondson, Donald; Fenster, Juliane R.; Blank, Thomas O. Meaning making and
psychological adjustment following cancer: The mediating roles of growth, life meaning, and restored just-
world beliefs. Journal of Consulting and Clinical Psychology, 76, 863-875 (2008).
221) Stockler MR,et al. Patient-reported outcome results from the open-label phase III AURELIA trial
evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J Clin Oncol. 32, 1309-
16 (2014).
222) Harano K, et al. Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly
64
paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment
for stage II-IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016). Ann Oncol. 25,
251-7 (2014).
223) Monk BJ, et al. Patient reported outcomes of a randomized, placebo-controlled trial of bevacizumab in
the front-line treatment of ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 128,
573-8 (2013).
224) Basch E, The missing voice of patients in drug-safety reporting. NEJM, 362, 865-869 (2010).
225) US Department of Health and Human Services Food and Drug Administration. Guidance for industry:
patient-reported outcome measures: use in medical product development to support labeling claims. 2009.
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf.
226) Donovan KA et al, Recommended patient reported core set of symptoms and quality of life domains
to measure in ovarian cancer treatment trials. JNCI, 106, 1-4 (2014).
227) Jensen SE, Kaiser K, Lacson L, Schink J, Cella D. Content validity of the NCCN-FACT ovarian
symptom index-18 (NFOSI-18). Gynecol Oncol. 136, 317-22 (2015).
228) Wenzel L, Huang HQ, Cella D, Walker JL, Armstrong DK; Gynecologic Oncology Group. Validation
of FACT/GOG-AD subscale for ovarian cancer-related abdominal discomfort: a Gynecologic Oncology
Group study. Gynecol Oncol. 110, 60-4 (2008).
229) Calhoun EA, Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, Cella D. Psychometric
evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity
(Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer. 13,
741-8 (2003).
230) Jenkins V et al, Patients’ and oncologists’ views on the treatment and care of advanced ovarian cancer
in the UK: results from the ADVOCATE study, BJC, 108, 2264-2271 (2013)
231) Cella DF et al. The Functional Assessment of Cancer Therapy scale: development and validation of
the general measure. JCO, 11, 570–579 (1993)
232) Basen-Engquist K, et al, Reliability and Validity of the Functional Assessment of Cancer Therapy-
Ovarian. JCO, 19, 1809-1817 (2001)
233) Havrilesky LJ et al, patient preferences in advanced or recurrent ovarian cancer. Cancer, 120:3651-
3659 (2010).
234) R. Chekerov, et al. Results of 641 patients of the NOGGO/ENGOT-ov22 survey: What are the
expectations of patients with ovarian cancer to a maintenance therapy? ESGO 2015.
235) US National Library of Medicine.
ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT02498600 (2015).
236) Glickman MS and Sawyers CL. Converting cancer therapies into cures; lessons from infectious
diseases. Cell 148, 1089-98 (2012).
237) Hanahan D and Weinberg RA. Hallmarks of Cancer: The next generation. Cell 144, 646-674 (2011).
238) Liu JF, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent
platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 15, 1207-14 (2014).
239) Matulonis U, et al. Phase I of Oral BKM120 and Oral Olaparib for High Grade Serous Ovarian
65
Cancer or Triple Negative Breast Cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr 2510).
240) pembro.nirap: US National Library of Medicine. ClinicalTrials.gov [online],
http://clinicaltrials.gov/ct2/show/NCT02657889 (2016).
241) Yap TA, Omlin A, de Bono JS. Development of Therapeutic Combinations Targeting Major Cancer
Signaling Pathways. J Clin Oncol 31, 1592-1605 (2013).
242) Paller CJ, et al. Design of phase I combination trials: recommendations of the Clinical Trial Design
Task Force of the NCI Investigational Drug Steering Committee. Clin Cancer Res. 20, 4210-7 (2014).
243) Herzog TJ, et al. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white
paper. Gynecol Oncol;132:8-17 (2014).
244) Matulonis UA, Oza AM, Ho TW, Ledermann JA. Intermediate clinical endpoints: a bridge between
progression-free survival and overall survival in ovarian cancer trials. Cancer; 121, 1737-46 (2015).
245) SOLO1: US National Library of Medicine.ClinicalTrials.gov [online],
http://clinicaltrials.gov/ct2/show/NCT01844986 (2013).
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